FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties

Wolfe, Sarah A.; Workman, Emily R.; Heaney, Chelcie F.; Niere, Farr; Namjoshi, Sanjeev V.; Cacheaux, Luisa P.; Farris, Sean P.; Drew, Michael R.; Zemelman, Boris V.; Harris, R. Adron; Raab‐Graham, Kimberly F.

doi:10.1038/ncomms12867

Cited by 32 publications

(59 citation statements)

References 67 publications

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“…The present findings expand upon past research which has linked alcohol to alterations in the molecular and epigenetic landscape in the cerebellum of postmortem AUD subjects (Gatta et al., ) and in the cerebellum of rodents exposed to perinatal EtOH (Guo et al., ; Qi et al., ) or chronic adult EtOH exposure (Auta et al., ). They also expand upon limited recent research illustrating a role for Fmr1 following EtOH exposure, albeit one that was, until now, exclusive to the hippocampus (Mulholland et al., ; Spencer et al., ; Wolfe et al., ). Fmr1 is a dynamic epigenetic target that can alter expression of hundreds of transcripts, but that itself may also be regulated by microRNAs (Kenny et al., ; Liu et al., ; Tan et al., ) or its own noncoding antisense RNA Fxr4 (Pastori et al., ; Peschansky et al., ).…”

Section: Discussionmentioning

confidence: 65%

“…This followed the previous reports of altered hippocampal FMRP expression in mice following chronic EtOH vapor treatment (Spencer et al., ). One other recent study has elucidated that EtOH‐induced translation of the GABA type B receptor protein in the hippocampus requires FMRP, as shown in wild‐type mice compared with Fmr1 ‐knockout mice (Wolfe et al., ). This finding supports the notion that FMRP facilitates increased expression of its targets as was shown with Psd95 (Ifrim et al., ; Todd et al., ; Zalfa et al., ).…”

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confidence: 96%

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Acute Ethanol Produces Ataxia and Induces Fmr1 Expression via Histone Modifications in the Rat Cerebellum

Dulman

Auta

Teppen

et al. 2019

Alcoholism Clin & Exp Res

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Background: The cerebellum is fundamental for motor coordination and therefore crucial in ethanol (EtOH)-induced ataxia. EtOH contributes to cerebellar pathophysiology. Fragile-X mental retardation protein (FMRP) is a complex regulator of RNA and synaptic plasticity implicated in fragile-X tremor and ataxia syndrome, a phenotype featuring increased Fmr1 mRNA expression. Recent studies have implicated glutamatergic targets of FMRP in hereditary cerebellar ataxias including the main cerebellar excitatory amino acid (Eaa1) transporter and a subtype of metabotropic glutamate receptor (Grm5). However, EtOH-induced changes in cerebellar Fmr1 expression and its epigenetic regulation have not been investigated. Here, we examined the effects of acute EtOH exposure on ataxic behavior, gene expression, and epigenetic regulation of the Fmr1 gene and its glutamatergic targets in the rat cerebellum.Methods: Male adult Sprague Dawley rats received acute EtOH (2 g/kg) intraperitoneally 1 hour prior to ataxic behavioral testing on the accelerating rotarod and were sacrificed immediately thereafter. Cerebellar tissues were analyzed for gene expression and epigenetic regulation of the Fmr1 gene and its glutamatergic targets in the rat cerebellum using real-time quantitative polymerase chain reaction (PCR) and chromatin immunoprecipitation.Results: Acute EtOH exposure caused marked ataxia on the accelerating rotarod test compared with saline-treated controls. This ataxic response was associated with increases in mRNA levels of Fmr1, postsynaptic density 95 (Psd95), Eaa1, and Grm5 in the cerebellum. In addition, we found increased H3K27 acetylation both at the promoter region of Fmr1 and at a proposed cyclic adenosine monophosphate (cAMP) response-element binding (CREB) site downstream of the Fmr1 transcription start site. Furthermore, acute EtOH exposure significantly increased Creb1 and the histone acetyltransferases (HAT) CREB binding protein (Cbp), and p300 mRNA transcripts.Conclusions: Overall, EtOH regulates cerebellar Fmr1 expression most likely via HAT-mediated increase in histone acetylation. We propose that FMRP regulation of glutamatergic transcripts plays an important role in disrupting the excitatory-inhibitory balance in the cerebellum underlying EtOHinduced ataxia.

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Section: Discussionmentioning

confidence: 65%

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confidence: 96%

Acute Ethanol Produces Ataxia and Induces Fmr1 Expression via Histone Modifications in the Rat Cerebellum

Dulman

Auta

Teppen

et al. 2019

Alcoholism Clin & Exp Res

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“…What might account for these initial observations that BLA-vHC silencing may have more robust effects on alcohol vs. sucrose drinking-related measures? One important difference between these two solutions is that sucrose is a natural reinforcer whose salience is mediated primarily by its taste properties whereas alcohol reinforcement is likely mediated by both its sensory and pharmacological properties [43,44]. Although beyond the scope of these studies, it is tempting to speculate that the greater efficacy of intra-vHC CNO on alcohol vs. sucrose drinking behaviors may be because inhibition of this BLA-vHC circuit diminishes the salience of the pharmacological effects of alcohol that reinforce appetitive and consummatory behaviors directed at this reinforcer (e.g.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus selectively reduces appetitive, but not consummatory, alcohol drinking-related behaviors

Ewin

Almonte

Bach

et al. 2019

Preprint

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HIGHLIGHTS The basolateral amygdala sends a monosynaptic projection to the ventral hippocampus  Inhibiting this circuit reduces anxiety-like behaviors in male Long Evans rats  Inhibition of this pathway also decreases operant alcohol drinking-related behaviors ABSTRACT Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the etiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from the BLA that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety-and fear-related behaviors. However, it is not known if this pathway influences alcohol drinking. Here, we employed a rodent operant drinking regimen that procedurally separates appetitive (seeking) and consummatory (intake) behaviors, chemogenetics, and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol drinking-related behaviors. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviors on the elevated plus-maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced both appetitive and consummatory alcohol drinking behaviors. Sucrose seeking and intake were also reduced following chemogenetic inhibition of this circuit, albeit to a lesser extent than alcohol drinking measures. Taken together, these findings provide the first indication that a BLA-vHC circuit may regulate both appetitive and consummatory alcohol drinking behaviors and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders.

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“…Animals were sacrificed 45 minutes after drug administration, and cortices were processed according to previously published methods 11,[26][27][28] .…”

Section: Immunoblottingmentioning

confidence: 99%

“…Primary neuronal hippocampal cultures were prepared from postnatal day 0-3 mouse pups from WT or Fmr1 KO mice according to previously published methods 11,[26][27][28] . Cells were plated between 70-100,000 per 12 mm on glass coverslips.…”

Section: Cell Culture and In Vitro Proximity Ligation Assay (Pla)mentioning

confidence: 99%

Role of FMRP in rapid antidepressant effects and synapse regulation

Heaney

Namjoshi

Uneri

et al. 2020

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Rapid antidepressants are novel treatments for major depressive disorder (MDD) and work by blocking N-methyl-aspartate receptors (NMDAR), which, in turn, activate the protein synthesis pathway regulated by mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Our recent work demonstrates that the RNA-binding protein Fragile X Mental Retardation Protein (FMRP) is downregulated in dendrites upon treatment with a rapid antidepressant. Here, we show that the behavioral effects of the rapid antidepressant Ro-25-6981 requires FMRP expression and promotes differential mRNA binding to FMRP in an mTORC1-dependent manner. Further, these mRNAs are identified to regulate transsynaptic signaling. Using a novel technique, we show that synapse formation underlying the behavioral effects of Ro-25-6981 require GABABR-mediated mTORC1 activity in WT animals. Finally, we demonstrate that in a clinically relevant animal model of Fragile X Syndrome (FXS), which lacks FMRP expression, GABABR activity is detrimental to the effects of Ro-25-6981. These effects are rescued when GABABRs are blocked in addition to treatment with Ro-25-6981, indicating that rapid antidepressants alone may not be an effective treatment for people with FXS and MDD.

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FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties

Cited by 32 publications

References 67 publications

Acute Ethanol Produces Ataxia and Induces Fmr1 Expression via Histone Modifications in the Rat Cerebellum

Acute Ethanol Produces Ataxia and Induces Fmr1 Expression via Histone Modifications in the Rat Cerebellum

Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus selectively reduces appetitive, but not consummatory, alcohol drinking-related behaviors

Role of FMRP in rapid antidepressant effects and synapse regulation

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