title: Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior.
abstract: Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of perturbed emotionality following fluoxetine exposure in early life.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Ambalika
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Parul
authors.initials: P
authors.lastname: Chachra
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Kennedy
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Pena
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Desouza
authors.affiliation: Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
authors.forename: Vidita A
authors.initials: VA
authors.lastname: Vaidya
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology* / Q000633:toxicity*; D001008:Anxiety Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D020148:Butyric Acid / Q000494:pharmacology; D003866:Depressive Disorder / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D004644:Emotions / Q000187:drug effects / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology* / Q000633:toxicity*; D015870:Gene Expression; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D006633:Histamine Antagonists / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D017207:Rats, Sprague-Dawley; D059467:Transcriptome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D006633:Histamine Antagonists; D005473:Fluoxetine; D020148:Butyric Acid; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases