Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior
Highlights
► Adult forebrain BDNF knockouts have smaller brains and many normal behaviors. ► Adult forebrain BDNF knockouts have reduced spatial learning and increased depression. ► Spine density is reduced by P84 in adult forebrain BDNF knockouts. ► Neuronal BDNF is necessary in adulthood to maintain normal spine density and behavior.
Introduction
BDNF, a member of the neurotrophin family of secreted proteins, was initially identified based upon its ability to support the survival of peripheral sensory neurons (Barde et al., 1982). Subsequent studies demonstrated the widespread expression of BDNF within the central nervous system (CNS) (Leibrock et al., 1989, Maisonpierre et al., 1990, Hofer et al., 1990), and its ability to influence the survival of many neuron types. BDNF has been shown to affect morphological features of specific neurons, such as soma size and dendritic arborization, as well as biochemical characteristics such as expression of biosynthetic enzymes and transporters for neurotransmitters (McAllister et al., 1999, Bibel, 2000). In addition, BDNF has been demonstrated to play a role in modulating synaptic transmission in many circuits within the brain, often potentiating synaptic strength, but sometimes reducing it (Tao and Poo, 2001, Lu et al., 2008, Waterhouse and Xu, 2009, Cunha et al., 2010, Yoshii and Constantine Paton, 2010). Given that neural activity can regulate BDNF expression and release, the fact that BDNF modulates synaptic transmission provides a molecular mechanism by which neural activity can modify the functional and structural features of neural circuitry (Thoenen, 1995, Cohen and Greenberg, 2008, Kuczewski et al., 2009, Greenberg et al., 2009, Cohen-Cory et al., 2010). Thus, this versatile signaling protein is utilized at many stages of life to accomplish diverse tasks in the development, maintenance, and plasticity of the brain. In addition, reduced BDNF expression has been identified in many neurodegenerative diseases, and augmenting BDNF signaling has received support as a potential therapeutic strategy (see Zuccato and Cattaneo, 2009, Nagahara and Tuszynski, 2011).
BDNF exerts many of its effects by binding to the receptor tyrosine kinase TrkB and triggering an intracellular kinase cascade (see Miller and Kaplan, 2001, Chao, 2003, Reichardt, 2006). BDNF can also exert effects on cells via the pan-neurotrophin receptor p75NTR, a member of the TNF receptor super family that binds pro-BDNF with much higher affinity than the mature form of BDNF, indicating that the processing of BDNF can be an important regulatory step (see Nykjaer et al., 2005, Underwood and Coulson, 2008, Barker, 2009, Greenberg et al., 2009, Teng et al., 2010). Both TrkB and p75 are expressed throughout the developing CNS (Buck et al., 1988, Yan and Johnson, 1988, Merlio et al., 1992). Expression of p75NTR becomes restricted primarily to basal forebrain cholinergic and striatal neurons in the adult forebrain (see Yan and Johnson, 1988, Kiss et al., 1988, Koh et al., 1989, Sobreviela et al., 1994, Lee et al., 1998), while TrkB remains widely expressed in the adult forebrain (Merlio et al., 1992, Valenzuela et al., 1993). Forebrain-specific mutants of BDNF or TrkB share many similar phenotypes and altering BDNF or TrkB in cultured hippocampal and cortical neurons leads to similar outcomes. These data together suggest that BDNF exerts many of its cortical and hippocampal effects in the intact, healthy brain via TrkB activation (see also Conover and Yancopoulos, 1997, McAllister et al., 1999).
Both BDNF and TrkB null mutant mice lose specific populations of sensory neurons through apoptotic cell death, indicating that BDNF is necessary for the survival of a subset of sensory neurons in the peripheral nervous system (PNS) (Klein et al., 1993, Ernfors et al., 1994, Jones et al., 1994, Huang and Reichardt, 2003). In contrast, only minor cell losses have been reported in the CNS of the null mutants (see Alcantara et al., 1997, Minichiello et al., 1999). However, the essential roles of BDNF and TrkB cannot be fully evaluated in null mutant mice, because they are retarded in their postnatal growth and die within the first few weeks of life, a period during which there is extensive neuronal differentiation, cell death, and synapse formation in the CNS. To circumvent the neonatal lethality of BDNF and TrkB null mutations and allow the study of CNS requirements for BDNF and TrkB signaling, several groups have used the Cre/lox system to engineer conditional BDNF and TrkB mutants that are viable into adulthood, and these mice have been useful in defining the functions of this signaling system in the forebrain (Minichiello et al., 1999, Xu et al., 2000a, Xu et al., 2000b, Rios et al., 2001, Vyssotski et al., 2002, Gorski et al., 2003a, Gorski et al., 2003b, Zörner et al., 2003, Baquet et al., 2004, Chen et al., 2005). By selective deletion of BDNF or TrkB in different cell populations using tissue-specific promoters or viruses to direct Cre recombinase expression, it is possible to define the precise pathways in which they act (e.g. Rios et al., 2001, Eisch et al., 2003, Monteggia et al., 2004, Heldt et al., 2007, Unger et al., 2007, Li et al., 2008, Graham et al., 2009, Lobo et al., 2010). Additionally, it is possible to distinguish the developmental vs. maintenance roles of BDNF and TrkB in the CNS by using strategies including antisense oligonucleotides, early-onset vs. late-onset promoters to direct expression of Cre recombinase, or by using a mutant version of TrkB that can be inhibited with a drug, (e.g. see Ma et al., 1998, Mizuno et al., 2000, Luikart et al., 2005, Chen et al., 2005, Chan et al., 2006, Johnson et al., 2008). The combination of these types of studies continues to shed light on the precise spatial and temporal roles of BDNF–TrkB signaling.
One of the fascinating aspects of the BDNF–TrkB signaling system is its relevance to a huge variety of mammalian behaviors, including learning and memory, depression, obesity, aggression, anxiety, and development of visual acuity (see Duman and Monteggia, 2006, Chen et al., 2006, Chen et al., 2008, Lu et al., 2008, Minichiello, 2009, Heimel et al., 2010, Castren and Rantamäki, 2010, Rios, 2011, Rosas-Vargas et al., 2011). Given the widespread expression of BDNF and TrkB in the CNS, their involvement in so many aspects of mammalian life is not surprising. However, the precise neural circuitry in which BDNF and TrkB act to influence specific behaviors is largely unknown. BDNF can potentially signal in anterograde, autocrine, paracrine or the classic retrograde manner (see Altar et al., 1997, Altar and DiStefano, 1998, Nawa and Takei, 2001), thus analysis of both ligand and receptor requirements is essential for understanding signaling direction in any given behavior.
Many of the analyses studying BDNF–TrkB signaling in behavior have relied upon null mutants in which this signaling pathway is affected during development as well as in the adult. There are low levels of BDNF expression in most of the CNS at birth and levels rise during the first few weeks of life, reaching maximum levels in young adulthood (Maisonpierre et al., 1990, Schoups et al., 1995, Katoh-Semba et al., 1998). It is important to determine whether BDNF–TrkB signaling has requirements for maintenance and plasticity of mature brain circuitry that are distinct from those during development. Here, we have performed both behavioral and anatomical analyses of an early adult-onset forebrain-specific BDNF mutant mouse. We find compelling similarities with an embryonic-onset forebrain-specific BDNF mutant mouse we previously described (Gorski et al., 2003a, Gorski et al., 2003b), suggesting that sustained adult BDNF expression is essential for maintenance of some of the same brain circuitry that is sensitive to the loss of BDNF during development.
Section snippets
Generation of forebrain-specific BDNF knockout mice
All animal procedures were approved by the University of Colorado Institutional Animal Care and Use Committee and conform to NIH guidelines. To generate mutant mice, CaMKcre mice (Xu et al., 2000a, Xu et al., 2000b) were mated to BDNFneo heterozygous mice (Jones et al., 1994) to create mice that were CaMKcre; BDNFneo. These CaMKcre; BDNFneo mice were heterozygous for the BDNF gene, but, as reported before, (Jones et al., 1994, Ernfors et al., 1994) the mice appeared similar to wild type though
CaMKcre can be used to deplete BDNF in the young adult forebrain
Although the CaMKcre transgene used in our studies has been previously characterized (Xu et al., 2000a, Xu et al., 2000b), some reports indicate that Cre transgenes can cause different tissue-specific patterns and timing of recombination with different floxed target genes. Thus, we determined the extent and timing of recombination occurring in CaMKcre; BDNFlox/+ mice at different ages using histochemistry. In BDNFlox mice, Cre-mediated recombination deletes the BDNF coding region and brings
Developmental and adult loss of BDNF lead to behavioral similarities
Here we have described specific behavioral and anatomical deficits in adult-onset BDNF mutant mice generated using Cre-loxP recombination. The behavioral phenotypes of these mutants are strikingly similar to those of an early-onset forebrain-specific BDNF mutant we previously described (Gorski et al., 2003b). Although the regional specificity of these two conditional mutants within the CNS is similar, it might have been anticipated that loss of BDNF during mid-embryogenesis in the early-onset
Conclusion
Our results demonstrate that continued expression of BDNF in the forebrain of the adult mouse is essential for some aspects of behavior, and for the maintenance of dendritic spine density on cortical pyramidal neurons. These observations are consistent with the hypothesis that reduced levels of BDNF in the adult human forebrain may contribute to the sensory and cognitive impairment, synapse loss, and neuronal atrophy that occur in diseases such as Alzheimer’s disease (Arancio and Chao, 2007).
Acknowledgments
This work was supported by the National Institutes of Health (EY014998). A.J.V. was supported by NIH KO1-NS01872 during a portion of this project. B.X. was supported by the Howard Hughes Medical Institute and NIH NS-P01-16033. We thank Louis Reichardt for supplying the CaMKcre/+ mice and for helpful suggestions. We thank Jeanne Wehner for assistance with behavioral experiments. There are no actual or potential conflicts of interest for any of the authors.
References (149)
- et al.
Neurotrophin trafficking by anterograde transport
Trends Neurosci
(1998) - et al.
Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons
Cell
(2008) - et al.
Neurotrophins, synaptic plasticity and dementia
Curr Opin Neurobiol
(2007) - et al.
Gender specific impact of BDNF signaling on stress-induced depression-like behavior
Biol Psychiatry
(2009) - et al.
Density and morphology of dendritic spines in mouse neocortex
Neuroscience
(2006) - et al.
Keeping Trk’ of antidepressant actions
Neuron
(2008) - et al.
Exercise and time-dependent benefits to learning and memory
Neuroscience
(2010) - et al.
Differential expression of the nerve growth factor receptor gene in multiple brain areas
Brain Res Dev Brain Res
(1988) - et al.
Examination of behavioral deficits triggered by targeting BDNF in fetal or postnatal brains of mice
Neuroscience
(2006) - et al.
A chemical-genetic approach to studying neurotrophin signaling
Neuron
(2005)
Intracerebroventricular administration of brain-derived neurotrophic factor in adult rats affects analgesia and spontaneous behaviour but not memory retention in a Morris Water Maze task
Neurosci Lett
Brain-derived neurotrophic factor is reduced in Alzheimer’s disease
Mol Brain Res
Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex
Neuroscience
Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments
Neurobiol Disease
A neurotrophic model for stress-related mood disorders
Biol Psychiatry
Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression
Biol Psychiatry
Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice
Neuroscience
Tropomyosin-related kinase B in the mesolimbic dopamine system: region-specific effects on cocaine reward
Biol Psychiatry
Dendritic spine plasticity: looking beyond development
Brain Res
A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition
Neuron
Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects
Brain Res
Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain
Exp Neurol
Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development
Cell
Age-related changes in levels of brain-derived neurotrophic factor in selected brain regions of rats, normal mice and senescence-accelerated mice. A comparison to those of nerve growth factor and neurotrophin-3
Neurosci Res
Immunohistochemical localization of cells containing nerve growth factor receptors in the different regions of the adult rat forebrain
Neuroscience
Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death
Cell
Localization of nerve growth factor receptor messenger RNA and protein in the adult rat brain
Exp Neurol
Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies
Pharmacol Ther
Localization of nerve growth factor, trkA and P75 immunoreactivity in the hippocampal formation and basal forebrain of adult rats
Neuroscience
TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment
Neuron
BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?
Neurobiol Learn Mem
NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression
Neuron
The amygdala and fear conditioning: has the nut been cracked?
Neuron
Neurotrophins and activity-dependent plasticity of cortical interneurons
Trends Neurosci
Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system
Neuroscience
Essential role for TrkB receptors in hippocampus-mediated learning
Neuron
TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death
J Neurosci
Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus
Cell Mol Neurobiol
Anterograde transport of brain-derived neurotrophic factor and its role in the brain
Nature
Anatomical and physiological plasticity of dendritic spines
Annu Rev Neurosci
Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor
J Neurosci
Purification of a new neurotrophic factor from mammalian brain
EMBO J
Whither proBDNF?
Nat Neurosci
Variant BDNF (Val66Met) impact on brain structure and function
Cogn Affect Behav Neurosci
Patterned expression of BDNF and NT-3 in the retina and anterior segment of the developing mammalian eye
Invest Ophthalmol Vis Sci
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress
Science
Dendritic spine dynamics
Annu Rev Physiol
Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system
Genes Dev
The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity
Dev Neurobiol
The distribution of brain-derived neurotrophic factor and its receptor trkB in parvlbumin-containing neurons of the rat visual cortex
Eur J Neurosci
Cited by (80)
Disruption of histone acetylation homeostasis triggers cognitive dysfunction in experimental diabetes
2023, Neurochemistry InternationalPro-neurogenic effects of Lilii Bulbus on hippocampal neurogenesis and memory
2023, Biomedicine and PharmacotherapyIntermittent fasting and cognitive performance – Targeting BDNF as potential strategy to optimise brain health
2022, Frontiers in NeuroendocrinologyMicroglia and BDNF at the crossroads of stressor related disorders: Towards a unique trophic phenotype
2021, Neuroscience and Biobehavioral Reviews