Gene expression and epigenetic processes in several brain regions regulate physiological processes such as cognitive functions and social behavior. MacroH2A1.1 is a ubiquitous variant of histone H2A that regulates cell stemness and differentiation in various organs. Whether macroH2A1.1 has a modulatory role in emotional behavior is unknown. Here, we employed macroH2A1.1 knock-out (-/- ) mice to perform a comprehensive battery of behavioral tests, and an assessment of hippocampal synaptic plasticity (long-term potentiation) accompanied by whole hippocampus RNA sequencing. MacroH2A1.1-/- mice exhibit a stunningly enhancement both of sociability and of active stress-coping behavior, reflected by the increased social behavior in social activity tests and higher mobility time in the forced swim test, respectively. They also display an increased hippocampal synaptic plasticity, accompanied by significant neurotransmission transcriptional networks changes. These results suggest that systemic depletion of histone macroH2A1.1 supports an epigenetic control necessary for hippocampal function and social behavior.

Centre for Behavioral Sciences and Mental Health Istituto Superiore di Sanità Rome Italy

Department of Biomedical and Biotechnological Sciences School of Medicine University of Catania Catania Italy

Division of Medicine University College London London UK

ERA Chair in Translational Stem Cell Biology Medical University Varna Varna Bulgaria

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

IRCCS Casa Sollievo della Sofferenza Bioinformatics Unit San Giovanni Rotondo Italy

National Centre for Drug Research and Evaluation Istituto Superiore di Sanità Rome Italy

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Buschbeck M, Hake SB. Variants of core histones and their roles in cell fate decisions, development and cancer. Nat Rev Mol Cell Biol. 2017;18:299-314.

Lo Re O, Vinciguerra M. Histone macroH2A1: a chromatin point of intersection between fasting, senescence and cellular regeneration. Genes. 2017;8(12):367.

Giallongo S, Rehakova D, Raffaele M, Lo Re O, Koutna I, Vinciguerra M. Redox and epigenetics in human pluripotent stem cells differentiation. Antioxid Redox Signal. 2021;34(4):335-349.

Hu Y, Chopra V, Chopra R, et al. Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse. Proc Natl Acad Sci U S A. 2011;108(41):17141-17146.

Guttula SV, Allam A, Gumpeny RS. Analyzing microarray data of Alzheimer's using cluster analysis to identify the biomarker genes. J Alzheimer's Dis. 2012;2012:649456.

Zovkic IB, Paulukaitis BS, Day JJ, Etikala DM, Sweatt JD. Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature. 2014;515:582-586.

Perche PY, Vourc'h C, Konecny L, et al. Higher concentrations of histone macroH2A in the Barr body are correlated with higher nucleosome density. Curr Biol. 2000;10:1531-1534.

Serrano M. Epigenetic cerebellar diseases. Handb Clin Neurol. 2018;155:227-244.

Bereshchenko O, Lo Re O, Nikulenkov F, et al. Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome. Clin Epigenetics. 2019;11:121.

Terzian AL, Drago F, Wotjak CT, Micale V. The dopamine and cannabinoid interaction in the modulation of emotions and cognition: assessing the role of cannabinoid CB1 receptor in neurons expressing dopamine D1 receptors. Front Behav Neurosci. 2011;5:49.

Monday HR, Younts TJ, Castillo PE. Long-term plasticity of neurotransmitter release: emerging mechanisms and contributions to brain function and disease. Annu Rev Neurosci. 2018;41:299-322.

Anastassiadis K, Fu J, Patsch C, et al. Dre recombinase, like Cre, is a highly efficient site-specific recombinase in E. coli, mammalian cells and mice. Dis Model Mech. 2009;2:508-515.

Uttl L, Szczurowska E, Hajkova K, et al. Behavioral and pharmacokinetic profile of indole-derived synthetic cannabinoids JWH-073 and JWH-210 as compared to the phytocannabinoid Delta(9)-THC in rats. Front Neurosci. 2018;12:703.

Stark T, Ruda-Kucerova J, Iannotti FA, et al. Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia. Neuropharmacology. 2019;146:212-221.

Drago F, Nicolosi A, Micale V, Lo Menzo G. Placebo affects the performance of rats in models of depression: is it a good control for behavioral experiments? Eur Neuropsychopharmacol. 2001;11:209-213.

Pamplona FA, Henes K, Micale V, Mauch CP, Takahashi RN, Wotjak CT. Prolonged fear incubation leads to generalized avoidance behavior in mice. J Psychiatr Res. 2011;45:354-360.

Direnberger S, Mues M, Micale V, et al. Biocompatibility of a genetically encoded calcium indicator in a transgenic mouse model. Nat Commun. 2012;3:1031.

Hazane F, Krebs MO, Jay TM, Le Pen G. Behavioral perturbations after prenatal neurogenesis disturbance in female rat. Neurotox Res. 2009;15:311-320.

Ferrante A, Pezzola A, Matteucci A, et al. The adenosine A2A receptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease. Neurobiol Dis. 2018;110:1-11.

Terzian AL, Micale V, Wotjak CT. Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex-dependent social interest in mice. Eur J Neuorsci. 2014;40:2293-2298.

Macri S, Ceci C, Onori MP, et al. Mice repeatedly exposed to Group-A beta-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon. Sci Rep. 2015;5:13257.

Zoratto F, Sbriccoli M, Martinelli A, Glennon JC, Macri S, Laviola G. Intranasal oxytocin administration promotes emotional contagion and reduces aggression in a mouse model of callousness. Neuropharmacology. 2018;143:250-267.

Yen YC, Mauch CP, Dahlhoff M, et al. Increased levels of conditioned fear and avoidance behavior coincide with changes in phosphorylation of the protein kinase B (AKT) within the amygdala in a mouse model of extremes in trait anxiety. Neurobiol Learn Mem. 2012;98:56-65.

Hofelmann D, di Benedetto B, Azad SC, Micale V, Wotjak CT, Rammes G. Lack of interaction of endocannabinoids and 5-HT(3) neurotransmission in associative fear circuits of the amygdala: evidence from electrophysiological and behavioural experiments. Brain Res. 2013;1527:47-56.

Micale V, Drago F, Noerregaard PK, Elling CE, Wotjak CT. The cannabinoid CB1 antagonist TM38837 with limited penetrance to the brain shows reduced fear-promoting effects in mice. Front Pharmacol. 2019;10:207.

Laviola G, Zoratto F, Ingiosi D, et al. Low empathy-like behaviour in male mice associates with impaired sociability, emotional memory, physiological stress reactivity and variations in neurobiological regulations. PLoS One. 2017;12:e0188907.

Murgatroyd C, Patchev AV, Wu Y, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci. 2009;12:1559-1566.

Micale V, Kucerova J, Sulcova A. Leading compounds for the validation of animal models of psychopathology. Cell Tissue Res. 2013;354:309-330.

Melnikova T, Savonenko A, Wang Q, et al. Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern. Neuroscience. 2006;141:1149-1162.

Smit-Rigter LA, Wadman WJ, van Hooft JA. Impaired social behavior in 5-HT(3A) receptor knockout mice. Front Behav Neurosci. 2010;4:169.

Zoratto F, Oddi G, Gori E, et al. Social modulation of risky decision-making in rats (Rattus norvegicus) and tufted capuchin monkeys (Sapajus spp.). Behav Brain Res. 2018;347:37-48.

De Filippis B, Chiodi V, Adriani W, et al. Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome. Front Behav Neurosci. 2015;9:86.

De Filippis D, Russo A, De Stefano D, et al. Palmitoylethanolamide inhibits rMCP-5 expression by regulating MITF activation in rat chronic granulomatous inflammation. Eur J Pharmacol. 2014;725:64-69.

Anderson WW, Collingridge GL. The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events. J Neurosci Methods. 2001;108:71-83.

Akbarian S, Chen RZ, Gribnau J, et al. Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex. Neurobiol Dis. 2001;8:784-791.

Kalman E, Keay KA. Hippocampal volume, social interactions, and the expression of the normal repertoire of resident-intruder behavior. Brain Behav. 2017;7:e00775.

Gerlai R. Behavioral tests of hippocampal function: simple paradigms complex problems. Behav Brain Res. 2001;125:269-277.

Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31-39.

Diogenes MJ, Costenla AR, Lopes LV, et al. Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology. 2011;36:1823-1836.

Barak B, Feng G. Neurobiology of social behavior abnormalities in autism and Williams syndrome. Nat Neurosci. 2016;19:647-655.

Sankoorikal GM, Kaercher KA, Boon CJ, Lee JK, Brodkin ES. A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains. Biol Psychiat. 2006;59:415-423.

Cryan JF, Holmes A. The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discovery. 2005;4:775-790.

Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8:955-960.

van der Kooij MA, Sandi C. Social memories in rodents: methods, mechanisms and modulation by stress. Neurosci Biobehav Rev. 2012;36:1763-1772.

Tzakis N, Holahan MR. Social memory and the role of the hippocampal CA2 region. Front Behav Neurosci. 2019;13:233.

Hitti FL, Siegelbaum SA. The hippocampal CA2 region is essential for social memory. Nature. 2014;508:88-92.

Meira T, Leroy F, Buss EW, Oliva A, Park J, Siegelbaum SA. A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics. Nat Commun. 2018;9:4163.

Freund TF, Buzsaki G. Interneurons of the hippocampus. Hippocampus. 1996;6:347-470.

Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S. Ventral CA1 neurons store social memory. Science. 2016;353:1536-1541.

Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5-21.

Lundbye CJ, Toft AKH, Banke TG. Inhibition of GluN2A NMDA receptors ameliorates synaptic plasticity deficits in the Fmr1(-/y) mouse model. J Physiol. 2018;596:5017-5031.

Glerup S, Bolcho U, Molgaard S, et al. SorCS2 is required for BDNF-dependent plasticity in the hippocampus. Mol Psychiatry. 2016;21:1740-1751.

Chalkiadaki K, Velli A, Kyriazidis E, et al. Development of the MAM model of schizophrenia in mice: sex similarities and differences of hippocampal and prefrontal cortical function. Neuropharmacology. 2019;144:193-207.

Nguyen PV, Duffy SN, Young JZ. Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice. J Neurophysiol. 2000;84:2484-2493.

Alexander GM, Farris S, Pirone JR, Zheng C, Colgin LL, Dudek SM. Social and novel contexts modify hippocampal CA2 representations of space. Nat Commun. 2016;7:10300.

Oliva A, Fernandez-Ruiz A, Leroy F, Siegelbaum SA. Hippocampal CA2 sharp-wave ripples reactivate and promote social memory. Nature. 2020;587:264-269.

Rao RP, von Heimendahl M, Bahr V, Brecht M. Neuronal responses to conspecifics in the ventral CA1. Cell Rep. 2019;27(12):3460-3472.e3.

Gu Y, McIlwain KL, Weeber EJ, et al. Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice. J Neurosci. 2002;22:2753-2763.

Wegener S, Buschler A, Stempel AV, et al. Defective synapse maturation and enhanced synaptic plasticity in Shank2 Deltaex7(-/-) Mice. eNeuro. 2018;5.

Campbell SL, van Groen T, Kadish I, Smoot LHM, Bolger GB. Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus. BMC Neurosci. 2017;18:77.

Fernandez AP, Serrano J, Tessarollo L, Cuttitta F, Martinez A. Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions. Proc Natl Acad Sci U S A. 2008;105:12581-12586.

Rozov AV, Valiullina FF, Bolshakov AP. Mechanisms of long-term plasticity of hippocampal GABAergic synapses. Biochemistry (Mosc). 2017;82:257-263.

Chilton JK, Guthrie S. Axons get ahead: Insights into axon guidance and congenital cranial dysinnervation disorders. Dev Neurobiol. 2017;77:861-875.

Lie DC, Colamarino SA, Song HJ, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370-1375.

Borghesan M, Fusilli C, Rappa F, et al. DNA hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Res. 2016;76:594-606.

Pazienza V, Panebianco C, Rappa F, et al. Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis. Epigenetics Chromatin. 2016;9:45.

Mizuno S, Hirota JN, Ishii C, Iwasaki H, Sano Y, Furuichi T. Comprehensive profiling of gene expression in the cerebral cortex and striatum of BTBRTF/ArtRbrc mice compared to C57BL/6J mice. Front Cell Neurosci. 2020;14:595607.

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