FMRP Mediates Chronic Ethanol-Induced Changes in NMDA, Kv4.2, and KChIP3 Expression in the Hippocampus

Overview

Journal Alcohol Clin Exp Res

Specialty Psychiatry

Date 2016 May 6

PMID 27147118

Citations 12

Authors

Kathryn B Spencer

Patrick J Mulholland

L Judson Chandler

Affiliations

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Abstract

Background: Exposure to chronic ethanol (EtOH) results in changes in the expression of proteins that regulate neuronal excitability. This study examined whether chronic EtOH alters the hippocampal expression and function of fragile X mental retardation protein (FMRP) and the role of FMRP in the modulation of chronic EtOH-induced changes in the expression of NMDA receptors and Kv4.2 channels.

Methods: For in vivo studies, C57BL/6J mice underwent a chronic intermittent EtOH (CIE) vapor exposure procedure. After CIE, hippocampal tissue was collected and subjected to immunoblot blot analysis of NMDA receptor subunits (GluN1, GluN2B), Kv4.2, and its accessory protein KChIP3. For in vitro studies, hippocampal slice cultures were exposed to 75 mM EtOH for 8 days. Following EtOH exposure, mRNAs bound to FMRP was measured. In a separate set of studies, cultures were exposed to an inhibitor of S6K1 (PF-4708671 [PF], 6 μM) in order to assess whether EtOH-induced homeostatic changes in protein expression depend upon changes in FMRP activity.

Results: Immunoblot blot analysis revealed increases in GluN1 and GluN2B but reductions in Kv4.2 and KChIP3. Analysis of mRNAs bound to FMRP revealed a similar bidirectional change observed as reduction of GluN2B and increase in Kv4.2 and KChIP3 mRNA transcripts. Analysis of FMRP further revealed that while chronic EtOH did not alter the expression of FMRP, it significantly increased phosphorylation of FMRP at the S499 residue that is known to critically regulate its activity. Inhibition of S6K1 prevented the chronic EtOH-induced increase in phospho-FMRP and changes in NMDA subunits, Kv4.2, and KChIP3. In contrast, PF had no effect in the absence of alcohol, indicating it was specific for the chronic EtOH-induced changes.

Conclusions: These findings demonstrate that chronic EtOH exposure enhances translational control of plasticity-related proteins by FMRP, and that S6K1 and FMRP activities are required for expression of chronic EtOH-induced homeostatic plasticity at glutamatergic synapses in the hippocampus.

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References

Bhattacharya A, Kaphzan H, Alvarez-Dieppa A, Murphy J, Pierre P, Klann E . Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron. 2012; 76(2):325-37. PMC: 3479445. DOI: 10.1016/j.neuron.2012.07.022. View

Lei Z, Deng P, Li Y, Xu Z . Downregulation of Kv4.2 channels mediated by NR2B-containing NMDA receptors in cultured hippocampal neurons. Neuroscience. 2009; 165(2):350-62. PMC: 2849736. DOI: 10.1016/j.neuroscience.2009.10.041. View

Zhang J, Hou L, Klann E, Nelson D . Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models. J Neurophysiol. 2009; 101(5):2572-80. PMC: 2681424. DOI: 10.1152/jn.90558.2008. View

Lee H, Ge W, Huang W, He Y, Wang G, Rowson-Baldwin A . Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. Neuron. 2011; 72(4):630-42. PMC: 3433402. DOI: 10.1016/j.neuron.2011.09.033. View

Napoli I, Mercaldo V, Pilo Boyl P, Eleuteri B, Zalfa F, De Rubeis S . The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell. 2008; 134(6):1042-54. DOI: 10.1016/j.cell.2008.07.031. View

Bonaccorso C, Spatuzza M, Di Marco B, Gloria A, Barrancotto G, Cupo A . Fragile X mental retardation protein (FMRP) interacting proteins exhibit different expression patterns during development. Int J Dev Neurosci. 2015; 42:15-23. DOI: 10.1016/j.ijdevneu.2015.02.004. View

Nicholas A, de Magalhaes J, Kraytsberg Y, Richfield E, Levanon E, Khrapko K . Age-related gene-specific changes of A-to-I mRNA editing in the human brain. Mech Ageing Dev. 2010; 131(6):445-7. PMC: 2915444. DOI: 10.1016/j.mad.2010.06.001. View

Zhang Y, Su P, Liang P, Liu T, Liu X, Liu X . The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit. J Neurosci. 2010; 30(22):7575-86. PMC: 6632380. DOI: 10.1523/JNEUROSCI.1312-10.2010. View

Xiong H, Kovacs I, Zhang Z . Differential distribution of KChIPs mRNAs in adult mouse brain. Brain Res Mol Brain Res. 2004; 128(2):103-11. DOI: 10.1016/j.molbrainres.2004.06.024. View

10.

Neasta J, Barak S, Ben Hamida S, Ron D . mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse. J Neurochem. 2014; 130(2):172-84. PMC: 4107045. DOI: 10.1111/jnc.12725. View

11.

Hoeffer C, Sanchez E, Hagerman R, Mu Y, Nguyen D, Wong H . Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 2012; 11(3):332-41. PMC: 3319643. DOI: 10.1111/j.1601-183X.2012.00768.x. View

12.

Chen E, Joseph S . Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins. Biochimie. 2015; 114:147-54. PMC: 4458461. DOI: 10.1016/j.biochi.2015.02.005. View

13.

Eadie B, Cushman J, Kannangara T, Fanselow M, Christie B . NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus. 2010; 22(2):241-54. DOI: 10.1002/hipo.20890. View

14.

Ceman S, ODonnell W, Reed M, Patton S, Pohl J, Warren S . Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet. 2003; 12(24):3295-305. DOI: 10.1093/hmg/ddg350. View

15.

Darnell J, Van Driesche S, Zhang C, Sharon Hung K, Mele A, Fraser C . FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011; 146(2):247-61. PMC: 3232425. DOI: 10.1016/j.cell.2011.06.013. View

16.

Trantham-Davidson H, Burnett E, Gass J, Lopez M, Mulholland P, Centanni S . Chronic alcohol disrupts dopamine receptor activity and the cognitive function of the medial prefrontal cortex. J Neurosci. 2014; 34(10):3706-18. PMC: 3942586. DOI: 10.1523/JNEUROSCI.0623-13.2014. View

17.

An W, Bowlby M, Betty M, Cao J, Ling H, Mendoza G . Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000; 403(6769):553-6. DOI: 10.1038/35000592. View

18.

Wang X, Peng C, Cai W, Xia J, Jin D, Dai Y . Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission. Eur J Neurosci. 2014; 39(10):1602-12. PMC: 4028396. DOI: 10.1111/ejn.12546. View

19.

Yun S, Trommer B . Fragile X mice: reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus. J Neurosci Res. 2010; 89(2):176-82. DOI: 10.1002/jnr.22546. View

20.

Becker H, Hale R . Repeated episodes of ethanol withdrawal potentiate the severity of subsequent withdrawal seizures: an animal model of alcohol withdrawal "kindling". Alcohol Clin Exp Res. 1993; 17(1):94-8. DOI: 10.1111/j.1530-0277.1993.tb00731.x. View