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Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.

ABSTRACT: Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.

SUBMITTER: Smith LN

PROVIDER: S-EPMC4052976 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.

Smith Laura N LN Jedynak Jakub P JP Fontenot Miles R MR Hale Carly F CF Dietz Karen C KC Taniguchi Makoto M Thomas Feba S FS Zirlin Benjamin C BC Birnbaum Shari G SG Huber Kimberly M KM Thomas Mark J MJ Cowan Christopher W CW

Neuron 20140501 3

Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function ...[more]

PMID: 24811383

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Project description:Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a novel mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine, and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine. Mice were treated for 7 days with daily injections of cocaine (20 mg/kg) and sacrificed 24 hrs later. Chromatin from bilateral punches of NAc was immunoprecipitated with an antibody against MEF2A as described previously with minor modifications (Renthal et al., 2007). Chromatin was sonicated to an average of ~500 bp and immunoprepitated with antibody against MEF2A (Santa Cruz, sc-313) or an IgG control (Upstate/Millipore). Antibody-bound chromatin was precipitated using Protein A beads from Upstate (06-157), which were washed with low salt, high salt, and LiCl buffers to remove non-specific DNA binding. Eluted chromatin was reverse-crosslinked at 65oC in the presence of proteinase K and EDTA. DNA was purified by chloroform extraction/ethanol precipitation and the enrichment of specific promoters was amplified by ligation-mediated PCR for genome-wide analysis (Sikder et al., 2006). Amplified DNA was then labeled with Cy3 (input-enriched) or Cy5 (MEF2-enriched) and hybridized to Nimblegen (Madison, WI) MM8 mouse promoter arrays. Bilateral nucleus accumbens from eight mice were pooled for microarray analysis.

Project description:Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb), and downstream ERK phosphorylation (dpERK) are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb) and downstream signaling via phosphorylation of the transcription factor MAD (pMAD) seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1) Wg and Jeb trans-synaptic signaling, and (2) synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

Dataset Information

Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.

Publications

Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.

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