Skip to main content

Advertisement

SpringerLink
Log in

Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was significantly increased. We concluded that apoptotic pathways are only partially affected in the pathogenesis of the Cc2d1a heterozygous mouse model.

Graphical abstract

A) Apoptosis is suppressed because the cell does not receive a death signal, or the receptor cannot activate the caspase 8 pathway despite the death signal. B) Since Caspase 8 and Caspase 3 expression is downregulated in our mouse model, the mechanism of apoptosis is not activated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Avrutsky MI, Troy CM (2021) Caspase-9: A Multimodal Therapeutic Target with Diverse Cellular Expression in Human Disease. Front Pharmacol 12:701301

    Article  CAS  Google Scholar 

  • Basel-Vanagaite L, Attia R, Yahav M, Ferland RJ, Anteki L, Walsh CA, Olender T, Straussberg R, Magal N, Taub E, Drasinover V, Alkelai A, Bercovich D, Rechavi G, Simon AJ, Shohat M (2006) The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet 43(3):203–210

    Article  CAS  Google Scholar 

  • Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472(7343):319–324

    Article  CAS  Google Scholar 

  • Cerulo G, Tafuri S, De Pasquale V, Rea S, Romano S, Costagliola A, Della Morte R, Avallone L, Pavone LM (2014) Serotonin activates cell survival and apoptotic death responses in cultured epithelial thyroid cells. Biochimie 105:211–215. https://doi.org/10.1016/j.biochi.2014.06.020

    Article  CAS  Google Scholar 

  • Crawley JN, Belknap JK, Collins A, Crabbe JC, Frankel W, Henderson N, Hitzemann RJ, Maxson SC, Miner LL, Silva AJ, Wehner JM, Wynshaw-Boris A, Paylor R (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132(2):107–124

    Article  CAS  Google Scholar 

  • Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110(3):483–495

    Article  CAS  Google Scholar 

  • Dana H, Tahtasakal R, Sener EF (2020a) Animal Models of Autism: A Perspective From Autophagy Mechanisms. J Translat Genet Genom 4:251–262

    Google Scholar 

  • Dana H, Bayramov KK, Delibasi N, Tahtasakal R, Bayramov R, Hamurcu Z, Sener EF (2020b) Disregulation of Autophagy in the Transgenerational Cc2d1a Mouse Model of Autism. Neuromolec Med 22(2):239–249

    Article  CAS  Google Scholar 

  • Dong D, Zielke HR, Yeh D, Yang P (2018) Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res 11(7):1076–1090

    Article  Google Scholar 

  • Eftekharian MM, Komaki A, Oskooie VK, Namvar A, Taheri M, Ghafouri-Fard S (2019) Assessment of Apoptosis Pathway in Peripheral Blood of Autistic Patients. J Mol Neurosci 69(4):588–596

    Article  CAS  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. https://doi.org/10.1080/01926230701320337

    Article  CAS  Google Scholar 

  • Endirlik BU, Bakır E, Ökçesiz A, Güler A, Hamurcu Z, Eken A, Dreij K, Gürbay A (2022) Investigation of the toxicity of a glyphosate-based herbicide in a human liver cell line: Assessing the involvement of Nrf2 pathway and protective effects of vitamin E and α-lipoic acid. Environ Toxicol Pharmacol 103999. https://doi.org/10.1016/j.etap.2022.103999

  • Hamurcu Z, Delibaşı N, Nalbantoglu U, Sener EF, Nurdinov N, Tascı B, Taheri S, Ozkul Y, Donmez-Altuntas H, Canatan H, Ozpolat B (2019) FOXM1 plays a role in autophagy by transcriptionally regulating Beclin-1 and LC3 genes in human triple-negative breast cancer cells. J Mol Med (berl) 97(4):491–508

    Article  CAS  Google Scholar 

  • Himanshu, Dharmila, Sarkar D, Nutan (2020) A Review of Behavioral Tests to Evaluate Different Types of Anxiety and Anti-anxiety Effects. Clin Psychopharmacol Neurosci 18(3):341–351

    Article  CAS  Google Scholar 

  • Keiser AA, Turnbull LM, Darian MA, Feldman DE, Song I, Tronson NC (2017) Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval. Neuropsychopharmacology 42(2):397–407

    Article  Google Scholar 

  • Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384(6607):368–372

    Article  CAS  Google Scholar 

  • Li H, Xiao Y, Han L, Jia Y, Luo S, Zhang D, Zhang L, Wu P, Xiao C, Kan W, Du J, Bao H (2021) Ganoderma lucidum polysaccharides ameliorated depression-like behaviors in the chronic social defeat stress depression model via modulation of Dectin-1 and the innate immune system. Brain Res Bull 171:16–24

    Article  Google Scholar 

  • Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ, Jiao S, Cho K, Sheng M (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141(5):859–871

    Article  CAS  Google Scholar 

  • Lo SC, Scearce-Levie K, Sheng M (2016) Characterization of social behaviors in caspase-3 deficient mice. Sci Rep 6:18335

    Article  CAS  Google Scholar 

  • Lossi L, Castagna C, Merighi A (2018) Caspase-3 Mediated Cell Death in the Normal Development of the Mammalian Cerebellum. Int J Mol Sci 19(12):3999

    Article  Google Scholar 

  • McCarthy MM (2016) Sex differences in the developing brain as a source of inherent risk. Dialogues Clin Neurosci 18:361–372

    Article  Google Scholar 

  • Mossa A, Manzini MC (2021) Molecular causes of sex-specific deficits in rodent models of neurodevelopmental disorders. J Neurosci Res 99(1):37–56

    Article  CAS  Google Scholar 

  • Oaks AW, Zamarbide M, Tambunan DE, Santini E, Di Costanzo S, Pond HL, Johnson MW, Lin J, Gonzalez DM, Boehler JF, Wu GK, Klann E, Walsh CA, Manzini MC (2017) Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits. Cereb Cortex 27(2):1670–1685

    Article  Google Scholar 

  • Ozkul Y, Taheri S, Bayram KK, Sener EF, Mehmetbeyoglu E, Oztop DB, Aybuga F, Tufan E, Bayram A, Dolu N, Zararsiz G, Kianmehr L, Beyaz F, Doganyigit Z, Cuzin F, Rassoulzadegan M (2020) A heritable profile of six miRNAs in autistic patients and mouse models. Sci Rep 10(1):9011

    Article  CAS  Google Scholar 

  • Patterson E, Ryan PM, Wiley N, Carafa I, Sherwin E, Moloney G, Franciosi E, Mandal R, Wishart DS, Tuohy K, Ross RP, Cryan JF, Dinan TG, Stanton C (2019) Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome. Sci Rep 9(1):16323

    Article  CAS  Google Scholar 

  • Savitskaya MA, Onishchenko GE (2015) Mechanisms of Apoptosis. Biochemistry (Mosc) 80(11):1393–1405

    Article  CAS  Google Scholar 

  • Schmidt B, Jacobson TK, Markus E (2009) Hippocampal and striatal dependent navigation: sex differences are limited to acquisition. Horm Behav 56(2):199–205

    Article  Google Scholar 

  • Seibenhener ML, Wooten MC (2015) Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 96:e52434

    Google Scholar 

  • Sener EF, Cıkılı Uytun M, Korkmaz Bayramov K, Zararsiz G, Oztop DB, Canatan H, Ozkul Y (2016) The roles of CC2D1A and HTR1A gene expressions in autism spectrum disorders. Metab Brain Disorders 31(3):613–619

    Article  CAS  Google Scholar 

  • Sener EF, Taheri S, Sahin MC, Korkmaz Bayramov K, Marasli MK, Zararsiz G, Mehmetbeyoglu E, Oztop DB, Canpolat M, Canatan H, Ozkul Y (2019) Altered Global mRNA Expressions of Pain and Aggression Related Genes in the Blood of Children with Autism Spectrum Disorders. J Mol Neurosci 67(1):89–96

    Article  CAS  Google Scholar 

  • Sener EF, Onal MG, Dal F, Nalbantoglu U, Ozkul Y, Canatan H, Oztop DB (2022) Novel alterations of CC2D1A as a candidate gene in a Turkish sample of patients with autism spectrum disorder. Int J Neurosci 132(11):1072–1079. https://doi.org/10.1080/00207454.2020.1860968

  • Shen C, Xiong WC, Mei L (2014) Caspase-3, shears for synapse pruning. Dev Cell 28(6):604–606

    Article  CAS  Google Scholar 

  • Styles M, Alsharshani D, Samara M, Alsharshani M, Khattab A, Qoronfleh MW, Al-Dewik NI (2020) Risk factors, diagnosis, prognosis and treatment of autism. Front Biosci (Landmark Ed) 25:1682–1717

    Article  CAS  Google Scholar 

  • Vuralli D, Wattiez AS, Russo AF, Bolay H (2019) Behavioral and cognitive animal models in headache research. J Headache Pain 20(1):11

    Article  Google Scholar 

  • Wang R, Tan J, Guo J, Zheng Y, Han Q, So KF, Yu J, Zhang L (2018) Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model. Front Cell Neurosci 12:500

    Article  CAS  Google Scholar 

  • Wei H, Alberts I, Li X (2014) The apoptotic perspective of autism. Int J Dev Neurosci 36:13–18

    Article  Google Scholar 

  • Zamarbide M, Mossa A, Muñoz-Llancao P, Wilkinson MK, Pond HL, Oaks AW, Manzini MC (2019) Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability. Biol Psychiatry 85(9):760–768

    Article  CAS  Google Scholar 

  • Zhao M, Raingo J, Chen ZJ, Kavalali ET (2011) Cc2d1a, a C2 domain containing protein linked to nonsyndromic mental retardation, controls functional maturation of central synapses. J Neurophysiol 105(4):1506–1515

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank to Selda Tasdemir and Celaleddin Goktas for animal care.

Funding

This study is supported by Research Fund of the Erciyes University (Project Number: TSA-2019–8757).

Author information

Authors and Affiliations

  1. Department of Medical Biology, Erciyes University Medical Faculty, 38039, Kayseri, Turkey

    Elif Funda Sener, Halime Dana, Reyhan Tahtasakal, Zuhal Hamurcu & Ahsen Guler

  2. Erciyes University Genome and Stem Cell Center (GENKOK), Kayseri, Turkey

    Elif Funda Sener, Halime Dana, Reyhan Tahtasakal, Zuhal Hamurcu, Ahsen Guler, Esra Tufan & Minoo Rassoulzadegan

  3. Department of Histology and Embryology, Bozok University Medical Faculty, 66100, Yozgat, Turkey

    Zuleyha Doganyigit

  4. INSERM-CNRS, IRCAN, Universite Cote d’Azur (UCA), 06107, Nice, France

    Minoo Rassoulzadegan

Authors
  1. Elif Funda Sener
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Halime Dana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reyhan Tahtasakal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zuhal Hamurcu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahsen Guler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Esra Tufan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zuleyha Doganyigit
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Minoo Rassoulzadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, EFS and MR; Methodology, EFS, ZH, HD, RT, ET, and AG; Investigation, EFS and HD; Formal Analysis, EFS, ZD and ZH; Writing – Original Draft, EFS, ZH and HD; Writing –Review & Editing, EFS and MR; Project Administration, EFS; Resources, EFS, HD, ZD; Funding Acquisition, EFS; Supervision, MR.

Corresponding author

Correspondence to Elif Funda Sener.

Ethics declarations

Ethical approval

All procedures carried out in mice were duly approved by the Animal Ethics Committee of Erciyes University. All research was performed in accordance with the relevant guidelines and regulations of Erciyes University Animal Ethics Committee, Kayseri, Turkey.

Consent to participate

Not applicable.

Consent for publication

It is affirmed that all the authors have agreed to the submission and publication of the research article and their inclusion of name(s) as co-author(s).

Conflicts of interest

The authors have no conflict of interest to declare that are relevant to the content of this article.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 1127 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sener, E.F., Dana, H., Tahtasakal, R. et al. Partial changes in apoptotic pathways in hippocampus and hypothalamus of Cc2d1a heterozygous. Metab Brain Dis 38, 531–541 (2023). https://doi.org/10.1007/s11011-022-01125-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-022-01125-y

Keywords

Search

Navigation