Abstract
Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.
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References
Abraham WC, Mason SE, Demmer J, Williams JM, Richardson CL, Tate WP, Lawlor PA, Dragunow M (1993) Correlations between immediate early gene induction and the persistence of long-term potentiation. Neuroscience 56:717–727
Agis-Balboa RC, Arcos-Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, Haladyniak U, Agbemenyah HY, Zovoilis A, Salinas-Riester G, Opitz L, Sananbenesi F, Fischer A (2011) A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J 30:4071–4083
Aicardi G, Argilli E, Cappello S, Santi S, Riccio M, Thoenen H, Canossa M (2004) Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 101:15788–15792
Aigner TG, Mishkin M (1986) The effects of physostigmine and scopolamine on recognition memory in monkeys. Behav Neural Biol 45:81–87
Aigner TG, Mitchell SJ, Aggleton JP, Delong MR, Struble RG, Price DL, Wenk GL, Pettigrew KD, Mishkin M (1991) Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques. Exp Brain Res 86:18–26
Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:121–145
Alfimova MV, Lezheiko TV, Gritsenko IK, Golimbet VE (2012) [Association of the insulin-like growth factor II (IGF2) gene with human cognitive functions]. Genetika 48:993–998
Altinbilek B, Manahan-Vaughan D (2009) A specific role for group II metabotropic glutamate receptors in hippocampal long-term depression and spatial memory. Neuroscience 158:149–158
Andero R, Ressler KJ (2012) Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav 11:503–512
Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461–469
Ango F, Robbe D, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L (2002) Homer-dependent cell surface expression of metabotropic glutamate receptor type 5 in neurons. Mol Cell Neurosci 20:323–329
Arai AC, Kessler M (2007) Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior. Curr Drug Targets 8:583–602
Aubert I, Rowe W, Meaney MJ, Gauthier S, Quirion R (1995) Cholinergic markers in aged cognitively impaired Long-Evans rats. Neuroscience 67:277–292
Auld DS, Mennicken F, Day JC, Quirion R (2001) Neurotrophins differentially enhance acetylcholine release, acetylcholine content and choline acetyltransferase activity in basal forebrain neurons. J Neurochem 77:253–262
Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68:209–245
Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, Jones PJ, Lindsley CW, Olive MF, Conn PJ (2009) mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34:2057–2071
Balkowiec A, Katz DM (2002) Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci 22:10399–10407
Balschun D, Manahan-Vaughan D, Wagner T, Behnisch T, Reymann KG, Wetzel W (1999) A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning. Learn Mem 6:138–152
Bank B, Deweer A, Kuzirian AM, Rasmussen H, Alkon DL (1988) Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells. Proc Natl Acad Sci U S A 85:1988–1992
Barco A, Pittenger C, Kandel ER (2003) CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets 7:101–114
Barg J, Belcheva MM, Rowinski J, Coscia CJ (1993) kappa-Opioid agonist modulation of [3H]thymidine incorporation into DNA: evidence for the involvement of pertussis toxin-sensitive G protein-coupled phosphoinositide turnover. J Neurochem 60:1505–1511
Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104
Barnes CA (2003) Long-term potentiation and the ageing brain. Philos Trans R Soc Lond B Biol Sci 358:765–772
Barnes CA, Rao G, Foster TC, McNaughton BL (1992) Region-specific age effects on AMPA sensitivity: electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1. Hippocampus 2:457–468
Barrett GL, Bennie A, Trieu J, Ping S, Tsafoulis C (2009) The chronology of age-related spatial learning impairment in two rat strains, as tested by the Barnes maze. Behav Neurosci 123:533–538
Barria A, Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48:289–301
Barria A, Muller D, Derkach V, Griffith LC, Soderling TR (1997) Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276:2042–2045
Bartus RT (2000) On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529
Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414
Baudry M, Bi X, Gall C, Lynch G (2011) The biochemistry of memory: the 26year journey of a ‘new and specific hypothesis’. Neurobiol Learn Mem 95:125–133
Baudry M, Chou MM, Bi X (2013) Targeting calpain in synaptic plasticity. Expert Opin Ther Targets 17:579–592
Baxter MG, Lanthorn TH, Frick KM, Golski S, Wan RQ, Olton DS (1994) D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats. Neurobiol Aging 15:207–213
Bedrosian TA, Herring KL, Weil ZM, Nelson RJ (2011) Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proc Natl Acad Sci U S A 108:11686–11691
Beique JC, Na Y, Kuhl D, Worley PF, Huganir RL (2011) Arc-dependent synapse-specific homeostatic plasticity. Proc Natl Acad Sci U S A 108:816–821
Belcheva MM, Vogel Z, Ignatova E, Avidor-Reiss T, Zippel R, Levy R, Young EC, Barg J, Coscia CJ (1998) Opioid modulation of extracellular signal-regulated protein kinase activity is ras-dependent and involves Gbetagamma subunits. J Neurochem 70:635–645
Bellone C, Nicoll RA (2007) Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55:779–785
Benoit CE, Rowe WB, Menard C, Sarret P, Quirion R (2011) Genomic and proteomic strategies to identify novel targets potentially involved in learning and memory. Trends Pharmacol Sci 32:43–52
Benveniste M, Mayer ML (1991) Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Two binding sites each for glutamate and glycine. Biophys J 59:560–573
Berry RJ, Bronson FH (1992) Life history and bioeconomy of the house mouse. Biol Rev Camb Philos Soc 67:519–550
Bertaso F, Roussignol G, Worley P, Bockaert J, Fagni L, Ango F (2010) Homer1a-dependent crosstalk between NMDA and metabotropic glutamate receptors in mouse neurons. PLoS One 5:e9755
Bikbaev A, Neyman S, Ngomba RT, Conn PJ, Nicoletti F, Manahan-Vaughan D (2008) MGluR5 mediates the interaction between late-LTP, network activity, and learning. PLoS One 3:e2155
Bilkei-Gorzo A, Erk S, Schurmann B, Mauer D, Michel K, Boecker H, Scheef L, Walter H, Zimmer A (2012) Dynorphins regulate fear memory: from mice to men. J Neurosci 32:9335–9343
Bilkei-Gorzo A, Mauer D, Michel K, Zimmer A (2014) Dynorphins regulate the strength of social memory. Neuropharmacology 77:406–413
Billard JM, Rouaud E (2007) Deficit of NMDA receptor activation in CA1 hippocampal area of aged rats is rescued by D-cycloserine. Eur J Neurosci 25:2260–2268
Billingsley ML, Kubena RK (1978) The effects of naloxone and picrotoxin on the sedative and anticonflict effects of benzodiazepines. Life Sci 22:897–906
Bird CM, Burgess N (2008) The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci 9:182–194
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39
Blot K, Kimura SI, Bai J, Kemp A, Manahan-Vaughan D, Giros B, Tzavara E, Otani S (2013) Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801. Cereb Cortex
Blum S, Moore AN, Adams F, Dash PK (1999) A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J Neurosci 19:3535–3544
Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R (2006) Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 51:213–225
Boess FG, De Vry J, Erb C, Flessner T, Hendrix M, Luithle J, Methfessel C, Riedl B, Schnizler K, van der Staay FJ, van Kampen M, Wiese WB, Koenig G (2007) The novel alpha7 nicotinic acetylcholine receptor agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(methoxy)phenyl]-1-benzofuran-2-carboxa mide improves working and recognition memory in rodents. J Pharmacol Exp Ther 321:716–725
Borgdorff AJ, Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417:649–653
Bortolotto ZA, Collett VJ, Conquet F, Jia Z, van der Putten H, Collingridge GL (2005) The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors. Neuropharmacology 49(Suppl 1):13–25
Bouwknecht JA, Paylor R (2002) Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav Brain Res 136:489–501
Bradley SR, Lameh J, Ohrmund L, Son T, Bajpai A, Nguyen D, Friberg M, Burstein ES, Spalding TA, Ott TR, Schiffer HH, Tabatabaei A, McFarland K, Davis RE, Bonhaus DW (2010) AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model. Neuropharmacology 58:365–373
Brakeman PR, Lanahan AA, O’Brien R, Roche K, Barnes CA, Huganir RL, Worley PF (1997) Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386:284–288
Bramham CR, Worley PF, Moore MJ, Guzowski JF (2008) The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J Neurosci 28:11760–11767
Bredt DS, Nicoll RA (2003) AMPA receptor trafficking at excitatory synapses. Neuron 40:361–379
Bresink I, Benke TA, Collett VJ, Seal AJ, Parsons CG, Henley JM, Collingridge GL (1996) Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells. Br J Pharmacol 119:195–204
Brightwell JJ, Gallagher M, Colombo PJ (2004) Hippocampal CREB1 but not CREB2 is decreased in aged rats with spatial memory impairments. Neurobiol Learn Mem 81:19–26
Brouillette J, Young D, During MJ, Quirion R (2007) Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABA(B) receptors in scopolamine-induced amnesia. J Neurochem 102:1978–1989
Bruno MA, Clarke PB, Seltzer A, Quirion R, Burgess K, Cuello AC, Saragovi HU (2004) Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA. J Neurosci 24:8009–8018
Brushfield AM, Luu TT, Callahan BD, Gilbert PE (2008) A comparison of discrimination and reversal learning for olfactory and visual stimuli in aged rats. Behav Neurosci 122:54–62
Bunce D, Batterham PJ, Mackinnon AJ, Christensen H (2012) Depression, anxiety and cognition in community-dwelling adults aged 70 years and over. J Psychiatr Res 46:1662–1666
Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40
Burke SN, Barnes CA (2010) Senescent synapses and hippocampal circuit dynamics. Trends Neurosci 33:153–161
Burke SN, Wallace JL, Nematollahi S, Uprety AR, Barnes CA (2010) Pattern separation deficits may contribute to age-associated recognition impairments. Behav Neurosci 124:559–573
Burke SN, Ryan L, Barnes CA (2012) Characterizing cognitive aging of recognition memory and related processes in animal models and in humans. Front Aging Neurosci 4:15
Cao X, Cui Z, Feng R, Tang YP, Qin Z, Mei B, Tsien JZ (2007) Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 25:1815–1822
Carey AN, Lyons AM, Shay CF, Dunton O, McLaughlin JP (2009) Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory. J Neurosci 29:4293–4300
Celikel T, Marx V, Freudenberg F, Zivkovic A, Resnik E, Hasan MT, Licznerski P, Osten P, Rozov A, Seeburg PH, Schwarz MK (2007) Select overexpression of homer1a in dorsal hippocampus impairs spatial working memory. Front Neurosci 1:97–110
Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415
Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM (2011) A critical role for IGF-II in memory consolidation and enhancement. Nature 469:491–497
Choleris E, Clipperton-Allen AE, Phan A, Kavaliers M (2009) Neuroendocrinology of social information processing in rats and mice. Front Neuroendocrinol 30:442–459
Choquet D, Triller A (2013) The dynamic synapse. Neuron 80:691–703
Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52:445–459
Christoffersen GR, Simonyi A, Schachtman TR, Clausen B, Clement D, Bjerre VK, Mark LT, Reinholdt M, Schmith-Rasmussen K, Zink LV (2008) MGlu5 antagonism impairs exploration and memory of spatial and non-spatial stimuli in rats. Behav Brain Res 191:235–245
Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL (2000) Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci 20:7258–7267
Ciccarelli A, Giustetto M (2014) Role of ERK signaling in activity-dependent modifications of histone proteins. Neuropharmacology 80C:34–44
Ciruela F, Soloviev MM, Chan WY, McIlhinney RA (2000) Homer-1c/Vesl-1L modulates the cell surface targeting of metabotropic glutamate receptor type 1alpha: evidence for an anchoring function. Mol Cell Neurosci 15:36–50
Clements JD, Westbrook GL (1991) Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron 7:605–613
Cleva RM, Olive MF (2011) Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. Molecules 16:2097–2106
Coalombo PJ, Wetsel WC, Gallagher M (1997) Spatial memory is related to hippocampal subcellular concentrations of calcium-dependent protein kinase C isoforms in young and aged rats. Proc Natl Acad Sci U S A 94:14195–14199
Codazzi F, DI Cesare A, Chiulli N, Albanese A, Meyer T, Zacchetti D, Grohovaz F (2006) Synergistic control of protein kinase Cgamma activity by ionotropic and metabotropic glutamate receptor inputs in hippocampal neurons. J Neurosci 26:3404–3411
Cole AJ, Saffen DW, Baraban JM, Worley PF (1989) Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340:474–476
Collett VJ, Collingridge GL (2004) Interactions between NMDA receptors and mGlu5 receptors expressed in HEK293 cells. Br J Pharmacol 142:991–1001
Collingridge GL, Volianskis A, Bannister N, France G, Hanna L, Mercier M, Tidball P, Fang G, Irvine MW, Costa BM, Monaghan DT, Bortolotto ZA, Molnar E, Lodge D, Jane DE (2013) The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64:13–26
Colombo PJ, Gallagher M (2002) Individual differences in spatial memory among aged rats are related to hippocampal PKCgamma immunoreactivity. Hippocampus 12:285–289
Coronas V, Durand M, Chabot JG, Jourdan F, Quirion R (2000) Acetylcholine induces neuritic outgrowth in rat primary olfactory bulb cultures. Neuroscience 98:213–219
Costa-Mattioli M, Monteggia LM (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16:1537–1543
Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N (2009) Translational control of long-lasting synaptic plasticity and memory. Neuron 61:10–26
Crawley JN (2008) Behavioral phenotyping strategies for mutant mice. Neuron 57:809–818
Cui Y, Jin J, Zhang X, Xu H, Yang L, Du D, Zeng Q, Tsien JZ, Yu H, Cao X (2011) Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice. PLoS One 6:e20312
Curcio CA, Hinds JW (1983) Stability of synaptic density and spine volume in dentate gyrus of aged rats. Neurobiol Aging 4:77–87
Danysz W, Parsons CG (2003) The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 18:S23–S32
Davis S, Laroche S (2006) Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: a review. Genes Brain Behav 5(Suppl 2):61–72
Davis CM, Moskovitz B, Nguyen MA, Tran BB, Arai A, Lynch G, Granger R (1997) A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors. Psychopharmacology (Berl) 133:161–167
Davis HP, Small SA, Stern Y, Mayeux R, Feldstein SN, Keller FR (2003) Acquisition, recall, and forgetting of verbal information in long-term memory by young, middle-aged, and elderly individuals. Cortex 39:1063–1091
Davis MC, Horan WP, Marder SR (2014) Psychopharmacology of the negative symptoms: current status and prospects for progress. Eur Neuropsychopharmacol 24:788–799
Deiana S, Platt B, Riedel G (2011) The cholinergic system and spatial learning. Behav Brain Res 221:389–411
Dere E, Huston JP, De Souza Silva MA (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 31:673–704
Derkach V, Barria A, Soderling TR (1999) Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc Natl Acad Sci U S A 96:3269–3274
Deupree DL, Bradley J, Turner DA (1993) Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol Aging 14:249–258
Deutsch JA (1971) The cholinergic synapse and the site of memory. Science 174:788–794
Dickinson BA, Jo J, Seok H, Son GH, Whitcomb DJ, Davies CH, Sheng M, Collingridge GL, Cho K (2009) A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-alpha. Mol Brain 2:18
Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140:823–833
Dong YN, Wu HY, Hsu FC, Coulter DA, Lynch DR (2006) Developmental and cell-selective variations in N-methyl-D-aspartate receptor degradation by calpain. J Neurochem 99:206–217
Dong Z, Bai Y, Wu X, Li H, Gong B, Howland JG, Huang Y, He W, Li T, Wang YT (2013) Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze. Neuropharmacology 64:65–73
Dore S, Kar S, Quirion R (1997) Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases. Trends Neurosci 20:326–331
Dosemeci A, Jaffe H (2010) Regulation of phosphorylation at the postsynaptic density during different activity states of Ca2+/calmodulin-dependent protein kinase II. Biochem Biophys Res Commun 391:78–84
Drachman DA (1977) Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 27:783–790
Drake CT, Terman GW, Simmons ML, Milner TA, Kunkel DD, Schwartzkroin PA, Chavkin C (1994) Dynorphin opioids present in dentate granule cells may function as retrograde inhibitory neurotransmitters. J Neurosci 14:3736–3750
Ducottet C, Belzung C (2005) Correlations between behaviours in the elevated plus-maze and sensitivity to unpredictable subchronic mild stress: evidence from inbred strains of mice. Behav Brain Res 156:153–162
Dudai Y (1996) Consolidation: fragility on the road to the engram. Neuron 17:367–370
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665
Duncan RS, Hwang SY, Koulen P (2005) Effects of Vesl/Homer proteins on intracellular signaling. Exp Biol Med (Maywood) 230:527–535
English JD, Sweatt JD (1996) Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J Biol Chem 271:24329–24332
Fagni L, Worley PF, Ango F (2002) Homer as both a scaffold and transduction molecule. Sci STKE 2002(137):re8
Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G (2007) Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J Neurosci 27:8031–8039
Fitzjohn SM, Doherty AJ, Collingridge GL (2008) The use of the hippocampal slice preparation in the study of Alzheimer’s disease. Eur J Pharmacol 585:50–59
Flood DG (1993) Critical issues in the analysis of dendritic extent in aging humans, primates, and rodents. Neurobiol Aging 14:649–654
Floresco SB, Jentsch JD (2011) Pharmacological enhancement of memory and executive functioning in laboratory animals. Neuropsychopharmacology 36:227–250
Foster KA, McLaughlin N, Edbauer D, Phillips M, Bolton A, Constantine-Paton M, Sheng M (2010) Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J Neurosci 30:2676–2685
Fowler SW, Walker JM, Klakotskaia D, Will MJ, Serfozo P, Simonyi A, Schachtman TR (2013) Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents. Neurobiol Learn Mem 99:25–31
Fox GB, Fan L, Levasseur RA, Faden AI (1998) Effect of traumatic brain injury on mouse spatial and nonspatial learning in the Barnes circular maze. J Neurotrauma 15:1037–1046
Frankiewicz T, Parsons CG (1999) Memantine restores long term potentiation impaired by tonic N-methyl-D-aspartate (NMDA) receptor activation following reduction of Mg2+ in hippocampal slices. Neuropharmacology 38:1253–1259
Frankiewicz T, Potier B, Bashir ZI, Collingridge GL, Parsons CG (1996) Effects of memantine and MK-801 on NMDA-induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices. Br J Pharmacol 117:689–697
Frankland PW, Bontempi B (2005) The organization of recent and remote memories. Nat Rev Neurosci 6:119–130
Frisardi V, Panza F, Farooqui AA (2011) Late-life depression and Alzheimer’s disease: the glutamatergic system inside of this mirror relationship. Brain Res Rev 67:344–355
Gallagher M, Burwell R, Burchinal M (1993) Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behav Neurosci 107:618–626
Gallagher M, Bizon JL, Hoyt EC, Helm KA, Lund PK (2003) Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment. Exp Gerontol 38:71–77
Gallagher SM, Daly CA, Bear MF, Huber KM (2004) Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1. J Neurosci 24:4859–4864
Ge Y, Dong Z, Bagot RC, Howland JG, Phillips AG, Wong TP, Wang YT (2010) Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci U S A 107:16697–16702
Geerts H (2012) alpha7 Nicotinic receptor modulators for cognitive deficits in schizophrenia and Alzheimer’s disease. Expert Opin Investig Drugs 21:59–65
Golden SA, Covington HE 3rd, Berton O, Russo SJ (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6:1183–1191
Gong R, Park CS, Abbassi NR, Tang SJ (2006) Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J Biol Chem 281:18802–18815
Grayson BE, Fitzgerald MF, Hakala-Finch AP, Ferris VM, Begg DP, Tong J, Woods SC, Seeley RJ, Davidson TL, Benoit SC (2014) Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy. Int J Obes (Lond) 38:349–356
Guan X, Dluzen DE (1994) Age related changes of social memory/recognition in male Fischer 344 rats. Behav Brain Res 61:87–90
Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20:3993–4001
Guzowski JF, Setlow B, Wagner EK, McGaugh JL (2001) Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268. J Neurosci 21:5089–5098
Guzowski JF, Timlin JA, Roysam B, McNaughton BL, Worley PF, Barnes CA (2005) Mapping behaviorally relevant neural circuits with immediate-early gene expression. Curr Opin Neurobiol 15:599–606
Hall J, Thomas KL, Everitt BJ (2000) Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3:533–535
Hall J, Thomas KL, Everitt BJ (2001) Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: selective activation of hippocampal CA1 neurons during the recall of contextual memories. J Neurosci 21:2186–2193
Halt AR, Dallapiazza RF, Zhou Y, Stein IS, Qian H, Juntti S, Wojcik S, Brose N, Silva AJ, Hell JW (2012) CaMKII binding to GluN2B is critical during memory consolidation. EMBO J 31:1203–1216
Hampson RE, Rogers G, Lynch G, Deadwyler SA (1998a) Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J Neurosci 18:2748–2763
Hampson RE, Rogers G, Lynch G, Deadwyler SA (1998b) Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J Neurosci 18:2740–2747
Han JH, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ, Josselyn SA (2007) Neuronal competition and selection during memory formation. Science 316:457–460
Hardingham GE, Arnold FJ, Bading H (2001) A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat Neurosci 4:565–566
Harrison FE, Reiserer RS, Tomarken AJ, McDonald MP (2006) Spatial and nonspatial escape strategies in the Barnes maze. Learn Mem 13:809–819
Harvey J, Balasubramaniam R, Collingridge GL (1993) Carbachol can potentiate N-methyl-D-aspartate responses in the rat hippocampus by a staurosporine and thapsigargin-insensitive mechanism. Neurosci Lett 162:165–168
Hashimoto K, Ishima T, Fujita Y, Matsuo M, Kobashi T, Takahagi M, Tsukada H, Iyo M (2008) Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective alpha7 nicotinic receptor agonist SSR180711. Biol Psychiatry 63:92–97
Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10:880–886
He X, Yang F, Xie Z, Lu B (2000) Intracellular Ca(2+) and Ca(2+)/calmodulin-dependent kinase II mediate acute potentiation of neurotransmitter release by neurotrophin-3. J Cell Biol 149:783–792
Hermans EJ, Battaglia FP, Atsak P, de Voogd LD, Fernandez G, Roozendaal B (2014) How the amygdala affects emotional memory by altering brain network properties. Neurobiol Learn Mem 112:2–16
Hiramatsu M, Watanabe E (2006) Dynorphin A (2–13) improves mecamylamine-induced learning impairment accompanied by reversal of reductions in acetylcholine release in rats. Neuropeptides 40:47–56
Hiramatsu M, Murasawa H, Nabeshima T, Kameyama T (1998) Effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairment in rats. J Pharmacol Exp Ther 284:858–867
Hongpaisan J, Alkon DL (2007) A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC. Proc Natl Acad Sci U S A 104:19571–19576
Hou L, Klann E (2004) Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24:6352–6361
Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736
Hudon C, Dore FY, Goulet S (2002) Spatial memory and choice behavior in the radial arm maze after fornix transection. Prog Neuropsychopharmacol Biol Psychiatry 26:1113–1123
Huganir RL, Nicoll RA (2013) AMPARs and synaptic plasticity: the last 25 years. Neuron 80:704–717
Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3:661–669
Isaac JT, Nicoll RA, Malenka RC (1995) Evidence for silent synapses: implications for the expression of LTP. Neuron 15:427–434
Itoh J, Ukai M, Kameyama T (1993) Dynorphin A-(1–13) markedly improves scopolamine-induced impairment of spontaneous alternation performance in mice. Eur J Pharmacol 236:341–345
Jiang HK, Owyang VV, Hong JS, Gallagher M (1989) Elevated dynorphin in the hippocampal formation of aged rats: relation to cognitive impairment on a spatial learning task. Proc Natl Acad Sci U S A 86:2948–2951
Jo J, Son GH, Winters BL, Kim MJ, Whitcomb DJ, Dickinson BA, Lee YB, Futai K, Amici M, Sheng M, Collingridge GL, Cho K (2010) Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nat Neurosci 13:1216–1224
Joels M, Fernandez G, Roozendaal B (2011) Stress and emotional memory: a matter of timing. Trends Cogn Sci 15:280–288
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531
Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S, Charnay P, Bozon B, Laroche S, Davis S (2001) A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci 4:289–296
Josselyn SA, Shi C, Carlezon WA Jr, Neve RL, Nestler EJ, Davis M (2001) Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J Neurosci 21:2404–2412
Kammermeier PJ, Worley PF (2007) Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors. Proc Natl Acad Sci U S A 104:6055–6060
Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658–1662
Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–391
Kar S, Chabot JG, Quirion R (1993) Quantitative autoradiographic localization of [125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol 333:375–397
Kar S, Seto D, Dore S, Hanisch U, Quirion R (1997) Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation. Proc Natl Acad Sci U S A 94:14054–14059
Kerr DS, Campbell LW, Hao SY, Landfield PW (1989) Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science 245:1505–1509
Kida S, Josselyn SA, Pena de Ortiz S, Kogan JH, Chevere I, Masushige S, Silva AJ (2002) CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5:348–355
Kirkwood A, Rozas C, Kirkwood J, Perez F, Bear MF (1999) Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J Neurosci 19:1599–1609
Kitraki E, Bozas E, Philippidis H, Stylianopoulou F (1993) Aging-related changes in IGF-II and c-fos gene expression in the rat brain. Int J Dev Neurosci 11:1–9
Kiyama Y, Manabe T, Sakimura K, Kawakami F, Mori H, Mishina M (1998) Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit. J Neurosci 18:6704–6712
Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241:835–837
Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323:838–845
Kolsch H, Wagner M, Bilkei-Gorzo A, Toliat MR, Pentzek M, Fuchs A, Kaduszkiewicz H, van den Bussche H, Riedel-Heller SG, Angermeyer MC, Weyerer S, Werle J, Bickel H, Mosch E, Wiese B, Daerr M, Jessen F, Maier W, Dichgans M (2009) Gene polymorphisms in prodynorphin (PDYN) are associated with episodic memory in the elderly. J Neural Transm 116:897–903
Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856–8860
Kotz CM, Weldon D, Billington CJ, Levine AS (2004) Age-related changes in brain proDynorphin gene expression in the rat. Neurobiol Aging 25:1343–1347
Kuehl-Kovarik MC, Magnusson KR, Premkumar LS, Partin KM (2000) Electrophysiological analysis of NMDA receptor subunit changes in the aging mouse cortex. Mech Ageing Dev 115:39–59
Labar KS, Cabeza R (2006) Cognitive neuroscience of emotional memory. Nat Rev Neurosci 7:54–64
Lamprecht R, Ledoux J (2004) Structural plasticity and memory. Nat Rev Neurosci 5:45–54
Landfield PW, Lynch G (1977) Impaired monosynaptic potentiation in in vitro hippocampal slices from aged, memory-deficient rats. J Gerontol 32:523–533
Landfield PW, Pitler TA (1984) Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. Science 226:1089–1092
Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM (2000) Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 20:8–21
Lee YS, Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126–140
Lee HK, Kameyama K, Huganir RL, Bear MF (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21:1151–1162
Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405:955–959
Lee SJ, Escobedo-Lozoya Y, Szatmari EM, Yasuda R (2009) Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458:299–304
Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009) A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther 122:302–311
Lenze EJ, Rogers JC, Martire LM, Mulsant BH, Rollman BL, Dew MA, Schulz R, Reynolds CF 3rd (2001) The association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research. Am J Geriatr Psychiatry 9:113–135
Levin ED, Rezvani AH (2002) Nicotinic treatment for cognitive dysfunction. Curr Drug Targets CNS Neurol Disord 1:423–431
Liao D, Hessler NA, Malinow R (1995) Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375:400–404
Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U, Kuhl D (1995) Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci U S A 92:5734–5738
Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13:169–182
Lissin DV, Gomperts SN, Carroll RC, Christine CW, Kalman D, Kitamura M, Hardy S, Nicoll RA, Malenka RC, Von Zastrow M (1998) Activity differentially regulates the surface expression of synaptic AMPA and NMDA glutamate receptors. Proc Natl Acad Sci U S A 95:7097–7102
Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623
Lu W, Roche KW (2012) Posttranslational regulation of AMPA receptor trafficking and function. Curr Opin Neurobiol 22:470–479
Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 17:5196–5205
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445
Luscher C, Huber KM (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:445–459
Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433–445
Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136
Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R (1997) Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp Neurol 145:89–92
Lynch G, Rex CS, Chen LY, Gall CM (2008) The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol 585:2–13
Magnusson KR, Brim BL, Das SR (2010) Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front Aging Neurosci 2:11
Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN (1989) An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340:554–557
Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126
Malinow R, Schulman H, Tsien RW (1989) Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245:862–866
Manahan-Vaughan D, Braunewell KH (2005) The metabotropic glutamate receptor, mGluR5, is a key determinant of good and bad spatial learning performance and hippocampal synaptic plasticity. Cereb Cortex 15:1703–1713
Manahan-Vaughan D, von Haebler D, Winter C, Juckel G, Heinemann U (2008) A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 18:125–134
Maren S, Quirk GJ (2004) Neuronal signalling of fear memory. Nat Rev Neurosci 5:844–852
Markham JA, McKian KP, Stroup TS, Juraska JM (2005) Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus. Hippocampus 15:97–103
Markowska AL (1999) Sex dimorphisms in the rate of age-related decline in spatial memory: relevance to alterations in the estrous cycle. J Neurosci 19:8122–8133
Markram H, Segal M (1990) Acetylcholine potentiates responses to N-methyl-D-aspartate in the rat hippocampus. Neurosci Lett 113:62–65
Marrone DF, Schaner MJ, McNaughton BL, Worley PF, Barnes CA (2008) Immediate-early gene expression at rest recapitulates recent experience. J Neurosci 28:1030–1033
Matsuda S, Mikawa S, Hirai H (1999) Phosphorylation of serine-880 in GluR2 by protein kinase C prevents its C terminus from binding with glutamate receptor-interacting protein. J Neurochem 73:1765–1768
McDaniel KL, Mundy WR, Tilson HA (1990) Microinjection of dynorphin into the hippocampus impairs spatial learning in rats. Pharmacol Biochem Behav 35:429–435
McGaugh JL (2000) Memory—a century of consolidation. Science 287:248–251
McGaugh JL (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 27:1–28
McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK, Lowell BB, Fanselow MS, Wilson MA, Tonegawa S (2007) Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317:94–99
McTighe SM, Cowell RA, Winters BD, Bussey TJ, Saksida LM (2010) Paradoxical false memory for objects after brain damage. Science 330:1408–1410
Menard C, Quirion R (2012a) Group 1 metabotropic glutamate receptor function and its regulation of learning and memory in the aging brain. Front Pharmacol 3:182
Menard C, Quirion R (2012b) Successful cognitive aging in rats: a role for mGluR5 glutamate receptors, homer 1 proteins and downstream signaling pathways. PLoS One 7:e28666
Menard C, Bastianetto S, Quirion R (2013a) Neuroprotective effects of resveratrol and epigallocatechin gallate polyphenols are mediated by the activation of protein kinase C gamma. Front Cell Neurosci 7:281
Menard C, Tse YC, Cavanagh C, Chabot JG, Herzog H, Schwarzer C, Wong TP, Quirion R (2013b) Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging. J Neurosci 33:12792–12804
Menard C, Herzog H, Schwarzer C, Quirion R (2014a) Possible role of dynorphins in Alzheimer’s disease and age-related cognitive deficits. Neurodegener Dis 13:82–85
Menard C, Quirion R, Bouchard S, Ferland G, Gaudreau P (2014b) Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging. Front Aging Neurosci 6:81
Menuz K, Stroud RM, Nicoll RA, Hays FA (2007) TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists. Science 318:815–817
Merrill DA, Chiba AA, Tuszynski MH (2001) Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats. J Comp Neurol 438:445–456
Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, da Silva B, Bramham CR (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27:10445–10455
Miller EK, Desimone R (1993) Scopolamine affects short-term memory but not inferior temporal neurons. Neuroreport 4:81–84
Miller FD, Kaplan DR (2003) Signaling mechanisms underlying dendrite formation. Curr Opin Neurobiol 13:391–398
Milner B, Penfield W (1955) The effect of hippocampal lesions on recent memory. Trans Am Neurol Assoc 42–8
Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H, Nabeshima T (2003) Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatry 8:217–224
Montgomery KE, Kessler M, Arai AC (2009) Modulation of agonist binding to AMPA receptors by 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546): differential effects across brain regions and GluA1-4/transmembrane AMPA receptor regulatory protein combinations. J Pharmacol Exp Ther 331:965–974
Monti B, Berteotti C, Contestabile A (2005) Dysregulation of memory-related proteins in the hippocampus of aged rats and their relation with cognitive impairment. Hippocampus 15:1041–1049
Mony L, Kew JN, Gunthorpe MJ, Paoletti P (2009) Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol 157:1301–1317
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60
Morris RG (1989) Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci 9:3040–3057
Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776
Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8:608–619
Mothet JP, Parent AT, Wolosker H, Brady RO Jr, Linden DJ, Ferris CD, Rogawski MA, Snyder SH (2000) D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 97:4926–4931
Muller L, Tokay T, Porath K, Kohling R, Kirschstein T (2013) Enhanced NMDA receptor-dependent LTP in the epileptic CA1 area via upregulation of NR2B. Neurobiol Dis 54:183–193
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567–584
Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150
Najavits LM, Gastfriend DR, Barber JP, Reif S, Muenz LR, Blaine J, Frank A, Crits-Christoph P, Thase M, Weiss RD (1998) Cocaine dependence with and without PTSD among subjects in the National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Am J Psychiatry 155:214–219
Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A, Carr CA, Johnston D, Wilson MA, Tonegawa S (2002) Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297:211–218
Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S (2003) Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38:305–315
Nelson TJ, Sun MK, Hongpaisan J, Alkon DL (2008) Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur J Pharmacol 585:76–87
Neumann ID (2008) Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 20:858–865
Neyman S, Manahan-Vaughan D (2008) Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro. Eur J Neurosci 27:1345–1352
Nguyen XV, Masse J, Kumar A, Vijitruth R, Kulik C, Liu M, Choi DY, Foster TC, Usynin I, Bakalkin G, Bing G (2005) Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance. Behav Brain Res 161:254–262
Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041
Niesen CE, Baskys A, Carlen PL (1988) Reversed ethanol effects on potassium conductances in aged hippocampal dentate granule neurons. Brain Res 445:137–141
Nikolarakis KE, Almeida OF, Yassouridis A, Herz A (1989) Presynaptic auto- and allelo-receptor regulation of hypothalamic opioid peptide release. Neuroscience 31:269–273
Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322
Nithianantharajah J, Murphy M (2009) Experience on the Barnes spatial maze influences PKCgamma levels in the hippocampus. Int J Neurosci 119:1014–1030
Noack J, Richter K, Laube G, Haghgoo HA, Veh RW, Engelmann M (2010) Different importance of the volatile and non-volatile fractions of an olfactory signature for individual social recognition in rats versus mice and short-term versus long-term memory. Neurobiol Learn Mem 94:568–575
O’Brien RJ, Kamboj S, Ehlers MD, Rosen KR, Fischbach GD, Huganir RL (1998) Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21:1067–1078
O’Donovan A, Slavich GM, Epel ES, Neylan TC (2013) Exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging. Neurosci Biobehav Rev 37:96–108
O’Keefe J, Dostrovsky J (1971) The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res 34:171–175
Olds JL, Anderson ML, McPhie DL, Staten LD, Alkon DL (1989) Imaging of memory-specific changes in the distribution of protein kinase C in the hippocampus. Science 245:866–869
Opazo P, Choquet D (2011) A three-step model for the synaptic recruitment of AMPA receptors. Mol Cell Neurosci 46:1–8
Page G, Khidir FA, Pain S, Barrier L, Fauconneau B, Guillard O, Piriou A, Hugon J (2006) Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes. Neurochem Int 49:413–421
Palmer MJ, Irving AJ, Seabrook GR, Jane DE, Collingridge GL (1997) The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology 36:1517–1532
Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008) Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59:70–83
Parsons RG, Gafford GM, Helmstetter FJ (2006) Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J Neurosci 26:12977–12983
Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111
Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145
Pichat P, Bergis OE, Terranova JP, Urani A, Duarte C, Santucci V, Gueudet C, Voltz C, Steinberg R, Stemmelin J, Oury-Donat F, Avenet P, Griebel G, Scatton B (2007) SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (II) efficacy in experimental models predictive of activity against cognitive symptoms of schizophrenia. Neuropsychopharmacology 32:17–34
Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bosl MR, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52:437–444
Ploski JE, Pierre VJ, Smucny J, Park K, Monsey MS, Overeem KA, Schafe GE (2008) The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is required for memory consolidation of pavlovian fear conditioning in the lateral amygdala. J Neurosci 28:12383–12395
Potier B, Rascol O, Jazat F, Lamour Y, Dutar P (1992) Alterations in the properties of hippocampal pyramidal neurons in the aged rat. Neuroscience 48:793–806
Potier B, Lamour Y, Dutar P (1993) Age-related alterations in the properties of hippocampal pyramidal neurons among rat strains. Neurobiol Aging 14:17–25
Potier B, Turpin FR, Sinet PM, Rouaud E, Mothet JP, Videau C, Epelbaum J, Dutar P, Billard JM (2010) Contribution of the d-serine-dependent pathway to the cellular mechanisms underlying cognitive aging. Front Aging Neurosci 2:1
Priel A, Kolleker A, Ayalon G, Gillor M, Osten P, Stern-Bach Y (2005) Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors. J Neurosci 25:2682–2686
Pyapali GK, Turner DA (1996) Increased dendritic extent in hippocampal CA1 neurons from aged F344 rats. Neurobiol Aging 17:601–611
Quirion R, Pert CB (1981) Dynorphins: similar relative potencies on mu, delta- and kappa-opiate receptors. Eur J Pharmacol 76:467–468
Quirion R, Wilson A, Rowe W, Aubert I, Richard J, Doods H, Parent A, White N, Meaney MJ (1995) Facilitation of acetylcholine release and cognitive performance by an M(2)-muscarinic receptor antagonist in aged memory-impaired. J Neurosci 15:1455–1462
Radulovic J, Tronson NC (2010) Molecular specificity of multiple hippocampal processes governing fear extinction. Rev Neurosci 21:1–17
Rapp PR, Gallagher M (1996) Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci U S A 93:9926–9930
Rapp PR, Deroche PS, Mao Y, Burwell RD (2002) Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits. Cereb Cortex 12:1171–1179
Rasmussen T, Schliemann T, Sorensen JC, Zimmer J, West MJ (1996) Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging 17:143–147
Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE (2011) Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36:782–792
Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017–3029
Roberge MC, Hotte-Bernard J, Messier C, Plamondon H (2008) Food restriction attenuates ischemia-induced spatial learning and memory deficits despite extensive CA1 ischemic injury. Behav Brain Res 187:123–132
Romano C, van den Pol AN, O’Malley KL (1996) Enhanced early developmental expression of the metabotropic glutamate receptor mGluR5 in rat brain: protein, mRNA splice variants, and regional distribution. J Comp Neurol 367:403–412
Roncarati R, Scali C, Comery TA, Grauer SM, Aschmi S, Bothmann H, Jow B, Kowal D, Gianfriddo M, Kelley C, Zanelli U, Ghiron C, Haydar S, Dunlop J, Terstappen GC (2009) Procognitive and neuroprotective activity of a novel alpha7 nicotinic acetylcholine receptor agonist for treatment of neurodegenerative and cognitive disorders. J Pharmacol Exp Ther 329:459–468
Rosen LB, Ginty DD, Weber MJ, Greenberg ME (1994) Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron 12:1207–1221
Rosenbrock H, Kramer G, Hobson S, Koros E, Grundl M, Grauert M, Reymann KG, Schroder UH (2010) Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator. Eur J Pharmacol 639:40–46
Rosenzweig ES, Rao G, McNaughton BL, Barnes CA (1997) Role of temporal summation in age-related long-term potentiation-induction deficits. Hippocampus 7:549–558
Rowe JW, Kahn RL (1997) Successful aging. Gerontologist 37:433–440
Rowe WB, Spreekmeester E, Meaney MJ, Quirion R, Rochford J (1998) Reactivity to novelty in cognitively-impaired and cognitively-unimpaired aged rats and young rats. Neuroscience 83:669–680
Rumpel S, Ledoux J, Zador A, Malinow R (2005) Postsynaptic receptor trafficking underlying a form of associative learning. Science 308:83–88
Russo VC, Gluckman PD, Feldman EL, Werther GA (2005) The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 26:916–943
Saito N, Kikkawa U, Nishizuka Y, Tanaka C (1988) Distribution of protein kinase C-like immunoreactive neurons in rat brain. J Neurosci 8:369–382
Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H et al (1995) Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 373:151–155
Sandin J, Nylander I, Georgieva J, Schott PA, Ogren SO, Terenius L (1998) Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect. Neuroscience 85:375–382
Sarter M, Parikh V (2005) Choline transporters, cholinergic transmission and cognition. Nat Rev Neurosci 6:48–56
Scali C, Giovannini MG, Bartolini L, Prosperi C, Hinz V, Schmidt B, Pepeu G (1997a) Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats. Eur J Pharmacol 325:173–180
Scali C, Giovannini MG, Prosperi C, Bartolini L, Pepeu G (1997b) Tacrine administration enhances extracellular acetylcholine in vivo and restores the cognitive impairment in aged rats. Pharmacol Res 36:463–469
Schacter DL (1999) The seven sins of memory. Insights from psychology and cognitive neuroscience. Am Psychol 54:182–203
Schoenbaum G, Nugent S, Saddoris MP, Gallagher M (2002) Teaching old rats new tricks: age-related impairments in olfactory reversal learning. Neurobiol Aging 23:555–564
Schwarzer C (2009) 30 years of dynorphins—new insights on their functions in neuropsychiatric diseases. Pharmacol Ther 123:353–370
Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20:11–21
Segal M (1982) Changes in neurotransmitter actions in the aged rat hippocampus. Neurobiol Aging 3:121–124
Shankar S, Teyler TJ, Robbins N (1998) Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J Neurophysiol 79:334–341
Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861
Sheng M, Cummings J, Roldan LA, Jan YN, Jan LY (1994) Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368:144–147
Shepherd JD, Bear MF (2011) New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14:279–284
Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643
Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52:475–484
Shinoe T, Matsui M, Taketo MM, Manabe T (2005) Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J Neurosci 25:11194–11200
Shiraishi-Yamaguchi Y, Furuichi T (2007) The homer family proteins. Genome Biol 8:206
Shukla VK, Lemaire S (1994) Non-opioid effects of dynorphins: possible role of the NMDA receptor. Trends Pharmacol Sci 15:420–424
Simmons ML, Terman GW, Drake CT, Chavkin C (1994) Inhibition of glutamate release by presynaptic kappa 1-opioid receptors in the guinea pig dentate gyrus. J Neurophysiol 72:1697–1705
Simpkins KL, Guttmann RP, Dong Y, Chen Z, Sokol S, Neumar RW, Lynch DR (2003) Selective activation induced cleavage of the NR2B subunit by calpain. J Neurosci 23:11322–11331
Smith AP, Henson RN, Dolan RJ, Rugg MD (2004) fMRI correlates of the episodic retrieval of emotional contexts. Neuroimage 22:868–878
Smith JS, Schindler AG, Martinelli E, Gustin RM, Bruchas MR, Chavkin C (2012) Stress-induced activation of the dynorphin/kappa-opioid receptor system in the amygdala potentiates nicotine conditioned place preference. J Neurosci 32:1488–1495
Soderling TR (1993) Calcium/calmodulin-dependent protein kinase II: role in learning and memory. Mol Cell Biochem 127–128:93–101
Staubli U, Rogers G, Lynch G (1994) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci U S A 91:777–781
Stern SA, Kohtz AS, Pollonini G, Alberini CM (2014) Enhancement of memories by systemic administration of insulin-like growth factor II. Neuropsychopharmacology 39(9):2179–2190
Steward O, Worley PF (2001) Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation. Neuron 30:227–240
Steward O, Wallace CS, Lyford GL, Worley PF (1998) Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron 21:741–751
Stoica L, Zhu PJ, Huang W, Zhou H, Kozma SC, Costa-Mattioli M (2011) Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc Natl Acad Sci U S A 108:3791–3796
Su SC, Tsai LH (2011) Cyclin-dependent kinases in brain development and disease. Annu Rev Cell Dev Biol 27:465–491
Sun MK, Alkon DL (2010) Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol Ther 127:66–77
Sun P, Lou L, Maurer RA (1996) Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV. J Biol Chem 271:3066–3073
Suzuki A, Fukushima H, Mukawa T, Toyoda H, Wu LJ, Zhao MG, Xu H, Shang Y, Endoh K, Iwamoto T, Mamiya N, Okano E, Hasegawa S, Mercaldo V, Zhang Y, Maeda R, Ohta M, Josselyn SA, Zhuo M, Kida S (2011) Upregulation of CREB-mediated transcription enhances both short- and long-term memory. J Neurosci 31:8786–8802
Svensson J, Diez M, Engel J, Wass C, Tivesten A, Jansson JO, Isaksson O, Archer T, Hokfelt T, Ohlsson C (2006) Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice. J Endocrinol 189:617–627
Swope SL, Moss SJ, Blackstone CD, Huganir RL (1992) Phosphorylation of ligand-gated ion channels: a possible mode of synaptic plasticity. FASEB J 6:2514–2523
Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W 3rd, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF, Kalivas PW (2004) Homer proteins regulate sensitivity to cocaine. Neuron 43:401–413
Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401:63–69
Tang SJ, Reis G, Kang H, Gingras AC, Sonenberg N, Schuman EM (2002) A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci U S A 99:467–472
Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183
Tombaugh GC, Rowe WB, Chow AR, Michael TH, Rose GM (2002) Theta-frequency synaptic potentiation in CA1 in vitro distinguishes cognitively impaired from unimpaired aged Fischer 344 rats. J Neurosci 22:9932–9940
Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS (2003) Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J Cell Biol 161:805–816
Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 62:405–496
Tse D, Langston RF, Kakeyama M, Bethus I, Spooner PA, Wood ER, Witter MP, Morris RG (2007) Schemas and memory consolidation. Science 316:76–82
Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338
Tsuda M, Suzuki T, Misawa M, Nagase H (1996) Involvement of the opioid system in the anxiolytic effect of diazepam in mice. Eur J Pharmacol 307:7–14
Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23:583–592
Tully T, Bourtchouladze R, Scott R, Tallman J (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2:267–277
Turner DA, Deupree DL (1991) Functional elongation of CA1 hippocampal neurons with aging in Fischer 344 rats. Neurobiol Aging 12:201–210
Turrigiano GG (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422–435
Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998) Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391:892–896
Tyszkiewicz JP, Gu Z, Wang X, Cai X, Yan Z (2004) Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C-dependent mechanism in pyramidal neurones of rat prefrontal cortex. J Physiol 554:765–777
Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS, McNaughton CH, Jacobson MA, Hutson PH (2009) Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 57:531–538
van der Kooij MA, Sandi C (2012) Social memories in rodents: methods, mechanisms and modulation by stress. Neurosci Biobehav Rev 36:1763–1772
Vazdarjanova A, McNaughton BL, Barnes CA, Worley PF, Guzowski JF (2002) Experience-dependent coincident expression of the effector immediate-early genes arc and Homer 1a in hippocampal and neocortical neuronal networks. J Neurosci 22:10067–10071
Vazdarjanova A, Ramirez-Amaya V, Insel N, Plummer TK, Rosi S, Chowdhury S, Mikhael D, Worley PF, Guzowski JF, Barnes CA (2006) Spatial exploration induces ARC, a plasticity-related immediate-early gene, only in calcium/calmodulin-dependent protein kinase II-positive principal excitatory and inhibitory neurons of the rat forebrain. J Comp Neurol 498:317–329
Wagner JJ, Terman GW, Chavkin C (1993) Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature 363:451–454
Walker JA, Olton DS (1979) Spatial memory deficit following fimbria-fornix lesions: independent of time for stimulus processing. Physiol Behav 23:11–15
Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D (2001) Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci 21:5484–5493
Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM (2008) Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59:84–97
Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88
Werther GA, Russo V, Baker N, Butler G (1998) The role of the insulin-like growth factor system in the developing brain. Horm Res 49(Suppl 1):37–40
West AE, Griffith EC, Greenberg ME (2002) Regulation of transcription factors by neuronal activity. Nat Rev Neurosci 3:921–931
Williams BJ, Bimonte-Nelson HA, Granholm-Bentley AC (2006) ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age. Psychopharmacology (Berl) 188:605–618
Wilson IA, Ikonen S, McMahan RW, Gallagher M, Eichenbaum H, Tanila H (2003) Place cell rigidity correlates with impaired spatial learning in aged rats. Neurobiol Aging 24:297–305
Wilson IA, Gallagher M, Eichenbaum H, Tanila H (2006) Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci 29:662–670
Winslow JT, Hastings N, Carter CS, Harbaugh CR, Insel TR (1993) A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365:545–548
Wisden W, Errington ML, Williams S, Dunnett SB, Waters C, Hitchcock D, Evan G, Bliss TV, Hunt SP (1990) Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron 4:603–614
Wishka DG, Walker DP, Yates KM, Reitz SC, Jia S, Myers JK, Olson KL, Jacobsen EJ, Wolfe ML, Groppi VE, Hanchar AJ, Thornburgh BA, Cortes-Burgos LA, Wong EH, Staton BA, Raub TJ, Higdon NR, Wall TM, Hurst RS, Walters RR, Hoffmann WE, Hajos M, Franklin S, Carey G, Gold LH, Cook KK, Sands SB, Zhao SX, Soglia JR, Kalgutkar AS, Arneric SP, Rogers BN (2006) Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure—activity relationship. J Med Chem 49:4425–4436
Wittmann W, Schunk E, Rosskothen I, Gaburro S, Singewald N, Herzog H, Schwarzer C (2009) Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone. Neuropsychopharmacology 34:775–785
Wong RW, Setou M, Teng J, Takei Y, Hirokawa N (2002) Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc Natl Acad Sci U S A 99:14500–14505
Wu GY, Deisseroth K, Tsien RW (2001) Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A 98:2808–2813
Wyllie DJ, Nicoll RA (1994) A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. Neuron 13:635–643
Xia M, Huang R, Guo V, Southall N, Cho MH, Inglese J, Austin CP, Nirenberg M (2009) Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory. Proc Natl Acad Sci U S A 106:2412–2417
Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ, Worley PF (1998) Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21:707–716
Xu J, Zhu Y, Contractor A, Heinemann SF (2009) mGluR5 has a critical role in inhibitory learning. J Neurosci 29:3676–3684
Yakovleva T, Marinova Z, Kuzmin A, Seidah NG, Haroutunian V, Terenius L, Bakalkin G (2007) Dysregulation of dynorphins in Alzheimer disease. Neurobiol Aging 28:1700–1708
Yang L, Mao L, Tang Q, Samdani S, Liu Z, Wang JQ (2004) A novel Ca2+-independent signaling pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. J Neurosci 24:10846–10857
Yang S, Megill A, Ardiles AO, Ransom S, Tran T, Koh MT, Lee HK, Gallagher M, Kirkwood A (2013a) Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats. J Neurosci 33:12670–12678
Yang SH, Sharrocks AD, Whitmarsh AJ (2013b) MAP kinase signalling cascades and transcriptional regulation. Gene 513:1–13
Yokoi M, Kobayashi K, Manabe T, Takahashi T, Sakaguchi I, Katsuura G, Shigemoto R, Ohishi H, Nomura S, Nakamura K, Nakao K, Katsuki M, Nakanishi S (1996) Impairment of hippocampal mossy fiber LTD in mice lacking mGluR2. Science 273:645–647
Yoshimura Y, Aoi C, Yamauchi T (2000) Investigation of protein substrates of Ca(2+)/calmodulin-dependent protein kinase II translocated to the postsynaptic density. Brain Res Mol Brain Res 81:118–128
Yoshimura Y, Shinkawa T, Taoka M, Kobayashi K, Isobe T, Yamauchi T (2002) Identification of protein substrates of Ca(2+)/calmodulin-dependent protein kinase II in the postsynaptic density by protein sequencing and mass spectrometry. Biochem Biophys Res Commun 290:948–954
Zhang WQ, Mundy WR, Thai L, Hudson PM, Gallagher M, Tilson HA, Hong JS (1991) Decreased glutamate release correlates with elevated dynorphin content in the hippocampus of aged rats with spatial learning deficits. Hippocampus 1:391–397
Zhang GR, Liu M, Cao H, Kong L, Wang X, O’Brien JA, Wu SC, Cook RG, Geller AI (2009) Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons. Hippocampus 19:413–423
Zhao X, Rosenke R, Kronemann D, Brim B, Das SR, Dunah AW, Magnusson KR (2009) The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory. Neuroscience 162:933–945
Zheng WH, Kar S, Quirion R (2000) Stimulation of protein kinase C modulates insulin-like growth factor-1-induced akt activation in PC12 cells. J Biol Chem 275:13377–13385
Zhou Y, Takahashi E, Li W, Halt A, Wiltgen B, Ehninger D, Li GD, Hell JW, Kennedy MB, Silva AJ (2007) Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. J Neurosci 27:13843–13853
Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443–455
Acknowledgments
This research was supported by grants from the Canadian Institutes of Health Research (CIHR) to R.Q. and the Quebec Network for Research on Aging (a network funded by the Fonds de recherche du Québec—Santé) to P.G. C.M. was the recipient of a postdoctoral fellowship from CIHR.
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Ménard, C., Gaudreau, P., Quirion, R. (2015). Signaling Pathways Relevant to Cognition-Enhancing Drug Targets. In: Kantak, K., Wettstein, J. (eds) Cognitive Enhancement. Handbook of Experimental Pharmacology, vol 228. Springer, Cham. https://doi.org/10.1007/978-3-319-16522-6_3
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