Hippocampal chromatin‐modifying enzymes are pivotal for scopolamine‐induced synaptic plasticity gene expression changes and memory impairment

Singh, Padmanabh; Konar, Arpita; Kumar, Ashish; Srivas, Sweta; Thakur, M. K.

doi:10.1111/jnc.13171

Cited by 52 publications

(48 citation statements)

References 49 publications

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“…In addition, in a model of iron-induced memory impairment, levels of H3K9 acetylation were significantly reduced in the hippocampus of rats with neonatal iron overload, but there were no changes in the acetylation levels of H3K14ac, H4K5ac, and H4K12ac [37]. A recent study has also shown that suppressed gene expression and impaired memory are related to the downregulation of histone acetylation of H3K9 and H3K14 [38]. H3K9 is likely to be a target of HDAC1 or 3, which play crucial roles as negative regulators of long-term memory [39].…”

Section: Discussionmentioning

confidence: 90%

Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

Jie

Xia

et al. 2018

Cell Physiol Biochem

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Background/Aims: Borna disease virus 1 (BoDV-1) infection induces cognitive impairment in rodents. Emerging evidence has demonstrated that Chromatin remodeling through histone acetylation can regulate cognitive function. In the present study, we investigated the epigenetic regulation of chromatin that underlies BoDV-1-induced cognitive changes in the hippocampus. Methods: Immunofluorescence assay was applied to detect BoDV-1 infection in hippocampal neurons and Sprague-Dawley rats models. The histone acetylation levels both in vivo and vitro were assessed by western blots. The acetylation-regulated genes were identified by ChIP-seq and verified by RT-qPCR. Cognitive functions were evaluated with Morris Water Maze test. In addition, Golgi staining, and electrophysiology were used to study changes in synaptic structure and function. Results: BoDV-1 infection of hippocampal neurons significantly decreased H3K9 histone acetylation level and inhibited transcription of several synaptic genes, including postsynaptic density 95 (PSD95) and brain-derived neurotrophic factor (BDNF). Furthermore, BoDV-1 infection of Sprague Dawley rats disrupted synaptic plasticity and caused spatial memory impairment. These rats also exhibited dysregulated hippocampal H3K9 acetylation and decreased PSD95 and BDNF protein expression. Treatment with the HDAC inhibitor, suberanilohydroxamic acid (SAHA), attenuated the negative effects of BoDV-1. Conclusion: Our results demonstrate that regulation of H3K9 histone acetylation may play an important role in BoDV-1-induced memory impairment, whereas SAHA may confer protection against BoDV-1-induced cognitive impairments. This study finds important

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Section: Discussionmentioning

confidence: 90%

Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

Jie

Xia

et al. 2018

Cell Physiol Biochem

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“…impairments, which typically use 100 μg/kg to 3 mg/kg doses of scopolamine (31)(32)(33). Second, the antidepressant-like effects were observed 24 hours after the final 25 μg/kg dose of scopolamine, at a time when the drug had largely been cleared.…”

Section: Figure 6 M1-achr Mediates Cholinergic Stimulation Of Sst Inmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

129

116

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R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

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“…Furthermore, we found that increase in DNA methylation and decrease in histone acetylation at neuronal immediate early genes (IEGs) promoter was correlated with decrease in their expression and consolidation of memory during amnesia (Singh et al . ; Srivas and Thakur ). As HDAC2 does not bind directly to methylated cytosines, we explored the SIN3A‐HDAC2 co‐repressor complex‐mediated regulation of memory consolidation during amnesia.…”

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confidence: 99%

Transcriptional co‐repressor SIN3A silencing rescues decline in memory consolidation during scopolamine‐induced amnesia

Srivas

Thakur

2018

Journal of Neurochemistry

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Epigenetic modifications through methylation of DNA and acetylation of histones modulate neuronal gene expression and regulate long-term memory. Earlier we demonstrated that scopolamine-induced decrease in memory consolidation is correlated with enhanced expression of hippocampal DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in mice. DNMT1 and HDAC2 act together by recruiting a co-repressor complex and deacetylating the chromatin. The catalytic activity of HDACs is mainly dependent on its incorporation into multiprotein co-repressor complexes, among which SIN3A-HDAC2 co-repressor is widely studied to regulate synaptic plasticity. However, the involvement of co-repressor complex in regulating memory loss or amnesia is unexplored. This study examines the role of co-repressor SIN3A in scopolamine-induced amnesia through epigenetic changes in the hippocampus. Scopolamine treatment remarkably enhanced hippocampal SIN3A expression in mice. To prevent such increase in SIN3A expression, we used hippocampal infusion of SIN3A-siRNA and assessed the effect of SIN3A silencing on scopolamine-induced amnesia. Silencing of SIN3A in amnesic mice reduced the binding of HDAC2 at neuronal immediate early genes (IEGs) promoter, but did not change the expression of HDAC2. Furthermore, it increased acetylation of H3K9 and H3K14 at neuronal IEGs (Arc, Egr1, Homer1 and Narp) promoter, prevented scopolamine-induced down-regulation of IEGs and improved consolidation of memory during novel object recognition task. These findings together suggest that SIN3A has a critical role in regulation of synaptic plasticity and might act as a potential therapeutic target to rescue memory decline during amnesia and other neuropsychiatric pathologies.

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Hippocampal chromatin‐modifying enzymes are pivotal for scopolamine‐induced synaptic plasticity gene expression changes and memory impairment

Cited by 52 publications

References 49 publications

Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Transcriptional co‐repressor SIN3A silencing rescues decline in memory consolidation during scopolamine‐induced amnesia

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