PMID- 25728234 OWN - NLM STAT- MEDLINE DCOM- 20160204 LR - 20211203 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 46 DP - 2015 May TI - Gadd45b is an epigenetic regulator of juvenile social behavior and alters local pro-inflammatory cytokine production in the rodent amygdala. PG - 60-9 LID - S0889-1591(15)00060-4 [pii] LID - 10.1016/j.bbi.2015.02.018 [doi] AB - Precise regulation of the epigenome during perinatal development is critical to the formation of species-typical behavior later in life. Recent data suggests that Gadd45b facilitates active DNA demethylation by recruiting proteins involved in base excision repair (BER), which will catalyze substitution of 5-methyl-cytosine (5mC) for an unmodified cytosine. While a role for Gadd45b has been implicated in both hippocampal and amygdalar learning tasks, to the best of our knowledge, no study has been done investigating the involvement of Gadd45b in neurodevelopmental programming of social behavior. To address this, we used a targeted siRNA delivery approach to transiently knock down Gadd45b expression in the neonatal rat amygdala. We chose to examine social behavior in the juvenile period, as social deficits associated with neurodevelopmental disorders tend to emerge in humans at an equivalent age. We find that neonatal Gadd45b knock-down results in altered juvenile social behavior and reduced expression of several genes implicated in psychiatric disorders, including methyl-CpG-binding protein 2 (MeCP2), Reelin, and brain derived neurotrophic factor (BDNF). We furthermore report a novel role for Gadd45b in the programmed expression of alpha2-adrenoceptor (Adra2a). Consistent with Gadd45b's role in the periphery, we also observed changes in the expression of pro-inflammatory cytokines interleukin-6 (Il-6) and interleukin-1beta (Il-1beta) in the amygdala, which could potentially mediate or exacerbate effects of Gadd45b knockdown on the organization of social behavior. These data suggest a prominent role for Gadd45b in the epigenetic programming of complex juvenile social interactions, and may provide insight into the etiology of juvenile behavioral disorders such as ADHD, autism, and/or schizophrenia. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Kigar, Stacey L AU - Kigar SL AD - Molecular and Cellular Pharmacology Program, University of Wisconsin-Madison, Madison, WI 53706, United States. FAU - Chang, Liza AU - Chang L AD - Department of Psychology, University of Wisconsin-Madison, Madison, WI 53706, United States. FAU - Auger, Anthony P AU - Auger AP AD - Department of Psychology, University of Wisconsin-Madison, Madison, WI 53706, United States; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53706, United States. Electronic address: apauger@wisc.edu. LA - eng GR - T32 GM008688/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20150226 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 0 (Antigens, Differentiation) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cell Adhesion Molecules, Neuronal) RN - 0 (Cytokines) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Gadd45b protein, rat) RN - 0 (Methyl-CpG-Binding Protein 2) RN - 0 (Nerve Tissue Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Adrenergic, alpha-2) RN - 0 (Reelin Protein) RN - 0 (Reln protein, rat) RN - EC 3.4.21.- (RELN protein, human) RN - EC 3.4.21.- (Serine Endopeptidases) SB - IM MH - Amygdala/*metabolism MH - Animals MH - Antigens, Differentiation/genetics/*metabolism MH - Anxiety/genetics/metabolism MH - Behavior, Animal/*physiology MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Cell Adhesion Molecules, Neuronal/genetics/metabolism MH - Cytokines/*metabolism MH - *Epigenesis, Genetic MH - Extracellular Matrix Proteins/genetics/metabolism MH - Gene Expression Regulation MH - Inflammation/genetics/metabolism MH - Methyl-CpG-Binding Protein 2/genetics/metabolism MH - Nerve Tissue Proteins/genetics/metabolism MH - RNA, Small Interfering MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Adrenergic, alpha-2/genetics/metabolism MH - Reelin Protein MH - Serine Endopeptidases/genetics/metabolism MH - *Social Behavior PMC - PMC4440808 MID - NIHMS680797 OTO - NOTNLM OT - Adra2a OT - Amygdala OT - Cytokines OT - Development OT - Epigenetics OT - Gadd45b OT - MeCP2 OT - Methylation OT - Reelin OT - Social play COIS- Financial interests The authors declare no competing financial interests. EDAT- 2015/03/03 06:00 MHDA- 2016/02/05 06:00 PMCR- 2015/05/21 CRDT- 2015/03/03 06:00 PHST- 2014/12/03 00:00 [received] PHST- 2015/02/17 00:00 [revised] PHST- 2015/02/20 00:00 [accepted] PHST- 2015/03/03 06:00 [entrez] PHST- 2015/03/03 06:00 [pubmed] PHST- 2016/02/05 06:00 [medline] PHST- 2015/05/21 00:00 [pmc-release] AID - S0889-1591(15)00060-4 [pii] AID - 10.1016/j.bbi.2015.02.018 [doi] PST - ppublish SO - Brain Behav Immun. 2015 May;46:60-9. doi: 10.1016/j.bbi.2015.02.018. Epub 2015 Feb 26.