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J Neurosci. 2015 Mar 4;35(9):3938-45. doi: 10.1523/JNEUROSCI.4499-14.2015. Epub 2015 Mar 4.

Homer protein-metabotropic glutamate receptor binding regulates endocannabinoid signaling and affects hyperexcitability in a mouse model of fragile X syndrome.

Author information

1
Department of Physiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201 tangaihui@gmail.com.
2
Department of Physiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201.

Abstract

The Fmr1 knock-out mouse model of fragile X syndrome (Fmr1(-/y)) has an epileptogenic phenotype that is triggered by group I metabotropic glutamate receptor (mGluR) activation. We found that a membrane-permeable peptide that disrupts mGluR5 interactions with long-form Homers enhanced mGluR-induced epileptiform burst firing in wild-type (WT) animals, replicating the early stages of hyperexcitability in Fmr1(-/y). The peptide enhanced mGluR-evoked endocannabinoid (eCB)-mediated suppression of inhibitory synapses, decreased it at excitatory synapses in WTs, but had no effect on eCB actions in Fmr1(-/y). At a low concentration, the mGluR agonist did not generate eCBs at excitatory synapses but nevertheless induced burst firing in both Fmr1(-/y) and peptide-treated WT slices. This burst firing was suppressed by a cannabinoid receptor antagonist. We suggest that integrity of Homer scaffolds is essential for normal mGluR-eCB functioning and that aberrant eCB signaling resulting from disturbances of this molecular structure contributes to the epileptic phenotype of Fmr1(-/y).

KEYWORDS:

DHPG; Fmr1; epilepsy; hippocampus; inhibitory synapses; seizure

PMID:
25740522
PMCID:
PMC4348189
DOI:
10.1523/JNEUROSCI.4499-14.2015
[Indexed for MEDLINE]
Free PMC Article

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