Hippocampal HDAC4 Contributes to Postnatal Fluoxetine-Evoked Depression-Like Behavior View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-03-25

AUTHORS

Ambalika Sarkar, Parul Chachra, Pamela Kennedy, Catherine J Pena, Lynette A Desouza, Eric J Nestler, Vidita A Vaidya

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. More... »

PAGES

2221-2232

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/npp.2014.73

DOI

http://dx.doi.org/10.1038/npp.2014.73

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24663010


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55 accompany perturbed emotionality
56 acetylation marks
57 adulthood
58 adulthood evokes
59 adults
60 animals
61 anxiety
62 anxiety-like behavior
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64 behavior
65 binding
66 butyrate
67 changes
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70 decline
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74 early life
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85 functional enrichment
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95 inhibitor sodium butyrate
96 kinase pathway
97 life
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99 mTOR
100 marks
101 mechanistic underpinnings
102 molecular changes
103 molecular signatures
104 nature
105 normalization
106 organic substances
107 overexpression
108 paradox
109 pathway
110 persistent depression
111 perturbed emotionality
112 postnatal
113 postnatal fluoxetine
114 promoter
115 protein kinase pathway
116 quantitative PCR studies
117 rat hippocampus
118 recruitment
119 regulation
120 repression
121 response
122 results
123 retreatment
124 role
125 signatures
126 sodium butyrate
127 specific molecular changes
128 specific transcripts
129 study
130 substances
131 transcriptional repression
132 transcripts
133 treatment
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