Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry

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Abstract

Despite the pronounced neurological deficits associated with mental retardation and autism, the degree to which neocortical circuit function is altered remains unknown. Here, we study changes in neocortical network function in the form of persistent activity states in the mouse model of fragile X syndrome-the Fmr1 knock-out (KO). Persistent activity states, or UP states, in the neocortex underlie the slow oscillation which occurs predominantly during slow-wave sleep, but may also play a role during awake states. We show that spontaneously occurring UPstates in the primary somatosensory cortex are38-67% longer inFmr1KO slices. In vivo, UPstates reoccur with a clear rhythmic component consistent with that of the slow oscillation and are similarly longer in the Fmr1 KO. Changes in neocortical excitatory circuitry likely play the major role in this alteration as supported by three findings: (1) longer UP states occur in slices of isolated neocortex, (2) pharmacologically isolated excitatory circuits in Fmr1 KO neocortical slices display prolonged bursting states, and (3) selective deletion of Fmr1 in cortical excitatory neurons is sufficient to cause prolonged UP states whereas deletion in inhibitory neurons has no effect. Excess signaling mediated bythe group 1 glutamate metabotropic receptor, mGluR5, contributes to the longer UPstates. Genetic reduction or pharmacological block adeofmGluR5 rescues the prolonged Upstate phenol type. Our result sreveal an alteration in network function in a mouse model of intellectual disability and autism which may impact both slow-wave sleep and information processing during waking states.

Original languageEnglish (US)
Pages (from-to)14223-14234
Number of pages12
JournalJournal of Neuroscience
Volume31
Issue number40
DOIs
StatePublished - Oct 5 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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