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Sexual dimorphism in fear learning memory due to epigenetic modification by Cdk5

Sexual dimorphism in fear learning memory due to epigenetic modification by Cdk5

Epigenetics of FLM, Stress, and NeuroDegenerative Disease

The epigenetic post-translational modifications of histone (hPTMs) is a notable cellular response mechanism to environmental stimuli2. Emerging reports point to the sexual dimorphism of epigenetic hPTMs within the neurobehavioral context of fear, learning, and memory (FLM), in neurodegenerative diseases, as well as stress- and trauma- related disorders3,4.

Developmental and Functional Roles of Cdk5

One important protein in cognitive functions is Cdk5, encoded by the Cyclin Dependent Kinase 5 (CDK5) gene of the cyclin-dependent kinase family5. Cdk5 plays pivotal roles in FLM and depression, as demonstrated in previous reports of its conditional deletion and histone acetylation in distinct brain regions of male mice6,7,8, hence positing the possibility of a similar mechanism in female mice.

Cdk5 has also been reported to be indispensable for proper brain development and brain function5, and its deregulation occurs in several neurodegenerative disorders such as Alzheimer's and Parkinson's disease. However, the current literature is reliant upon findings performed in transgenics and conditional knockout mice9,10,11 and remains divided on the precise role of Cdk5 in FLM, especially the precise molecular mechanisms underlying sex-specific epigenetic modulation.

Introducing Society for Neuroscience 2018 Travel Grant Winner, Dr. Ajinkya Sase

Taconic Biosciences is excited to award Dr. Ajinkya Sase with a travel grant to the Society for Neuroscience (SfN 2018) conference for his presentation, "Targeted Neuroepigenetic Editing of Cdk5 Regulates Chronic Stress". Dr. Sase is a talented epigeneticist who is passionate about improving human health by elucidating complex neurobiological mechanisms underlying neurobehavioral disorders. The findings of his presentation and research in Heller lab at ITMAT and Epigenetics Institute of the University of Pennsylvania were accepted in the Biological Psychiatry shortly after the conference1.

Sex-Variant Responses to Fear Conditioning and Memory

To investigate the sex-specific epigenetic mechanisms of FML, Dr. Ajinkya Sase and his co-workers utilized a novel targeted epigenetic editing approach within the hippocampus of eight- to ten-week-old wild-type C57BL6/J mice to clarify the causal relationship of chromatin modification to Cdk5 expression, followed by specific behavioural tests for fear conditioning and memory retrieval of these mice.

“A key advantage of targeted epigenetic modulation is that it is neuron specific and mimics experience driven epigenetic changes helping understand diseases of fear learning and memory.”
–Dr. Sase

The authors demonstrated that the epigenetically-modified female mice exhibited lower long-term fear memory retrieval (LT-FMR) than male mice that is consistent with the literature12,13, which suggests female-specific mechanism of fear memory protection. Moreover, they observed a sex-specific activation and epigenetic regulation of Cdk5 expression following LT-FLM retrieval.

Female-Specific Increase in Phosphorylated-Tau Protein

This behavior was associated with a targeted histone acetylation of the Cdk5 promoter, with increased Cdk5 expression in both sexes but attenuated short- and long-term memory retrieval in female mice only. Furthermore, only epigenetically-modified female mice exhibited attenuated (short & long term) fear memory retrieval, which was accompanied by a female-specific increase in phosphorylated-Tau protein.

The female-specific neurological effects of hyperphosphorylated Tau are well documented, with known effects on microtubule dynamics, axonal transport, and neurite outgrowth, sex-biased effects on the hippocampus, and neurodegenerative pathologies.

Application to Neurodegenerative, Stress-, and Trauma-Related Disorders

The epigenetic editing of Cdk5 (in the murine hippocampus) uncovered a female-specific role of its activation to attenuate fear L&M retrieval, which may be linked to sex-specific Cdk5 functions such as phosphorylation of Tau in the female hippocampus or activity on downstream target proteins that modulate learning and memory.

Sase and co-authors propose a model in which Cdk5 acetylation, expression, and subsequent downstream target phosphorylation is sex-specifically regulated. The current findings support the utility of targeted spatio-temporal epigenetic editing in the brains of current mouse models to investigate sex-specific roles of gene-of-interest (GOI) in neuro-developmental, -behavioural, and -degenerative disorders.

Future studies are required to determine the extent of sex-specific downstream targeting by GOI, such as Cdk5, to clarify the precise role of Tau and other targets in FLM to improve our understanding of related clinical disorders such as neurodegenerative diseases and stress- and trauma- related disorders.

1. Sase AS, Lombroso SI, Santhumayor BA, Wood RR, Lim CJ, Neve RL, Heller EA. Sex-specific regulation of fear memory by targeted epigenetic editing of Cdk5. Biological Psychiatry. 2018 Dec. Epublished.
2. Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P. Decoding the epigenetic language of neuronal plasticity. Neuron. 2008 Dec 26;60(6):961-74.
3. Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Feb 29;483(7388):222-6.
4. Malvaez M, Mhillaj E, Matheos DP, Palmery M, Wood MA. CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors. J Neurosci. 2011 Nov 23;31(47):16941-8.
5. Shah K, Lahiri DK. Cdk5 activity in the brain - multiple paths of regulation. J Cell Sci. 2014 Jun 1;127(Pt 11):2391-400. doi: 10.1242/jcs.147553. Review.
6. Heller EA, Hamilton PJ, Burek DD, Lombroso SI, Peña CJ, Neve RL, Nestler EJ. Targeted Epigenetic Remodeling of the Cdk5 Gene in Nucleus Accumbens Regulates Cocaine- and Stress-Evoked Behavior. J Neurosci. 2016 Apr 27;36(17):4690-7.
7. Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA. Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci. 2007 Jul;10(7):880-886.
8. Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH. A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci. 2007 Aug;10(8):1012-9.
9. Luo F, Zhang J, Burke K, Romito-DiGiacomo RR, Miller RH, Yang Y. Oligodendrocyte-specific loss of Cdk5 disrupts the architecture of nodes of Ranvier as well as learning and memory. Exp Neurol. 2018 Aug;306:92-104.
10. Plattner F, Hernández A, Kistler TM, Pozo K, Zhong P, Yuen EY, Tan C, Hawasli AH, Cooke SF, Nishi A, Guo A, Wiederhold T, Yan Z, Bibb JA. Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron. 2014 Mar 5;81(5):1070-1083.
11. Su SC, Rudenko A, Cho S, Tsai LH. Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment. Neurobiol Learn Mem. 2013 Oct;105:54-62.
12. Yagi S, Galea LAM. Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology. 2019 Jan;44(1):200-213.
13. Lebron-Milad K, Abbs B, Milad MR, Linnman C, Rougemount-Bücking A, Zeidan MA, Holt DJ, Goldstein JM. Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry. Biol Mood Anxiety Disord. 2012 Apr 16;2:7.

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