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Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmrl knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmrl KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, Hla, rescues many phenotypes of Fmrl KO mice. These results suggested that disruption of mGlu5- Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5,(/R) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5R/,i mice mimicked multiple phenotypes of Fmrl KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. [ABSTRACT FROM AUTHOR]

In the mouse model of Fragile X syndrome, the Fmrl knock-out, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, we performed recordings in acutely prepared slices obtained from Fmrl "mosaic" mice, where Fmrl is deleted in about half of all neurons, and we found that loss of presynaptic, but not postsynaptic, Fmrl fully recapitulates the deficit. The change in connection strength is primarily due to a decrease in release probability indicating that FMRP normally positively regulates these processes. This change in presynaptic neurotransmitter release is observed both in the mosaic mice and in the constitutive Fmrl knock-out mice. Manipulations in release probability enabled both the mimic and rescue of the impaired function in this synaptic pathway. Loss of presynaptic Fmrl has no effect on excitatory synapses onto excitatory neurons, indicating a target cell-specific function for presynaptic FMRP. Finally, we demonstrate that the excitation decrement onto FS neurons also exists in layer 5 of the Fmrl knock-out, suggesting a widespread role for presynaptic Fmrl in the excitation of inhibitory neurons. In summary, we identify a novel function for presynaptic FMRP in promoting presynaptic neurotransmitter release, and we show that loss of this function accounts for impaired excitation of neocortical FS inhibitory neurons. These changes may contribute to the cognitive dysfunction and circuit hyperexcitability associated with Fragile X syndrome, including patients with complete deletion of FMRP and those with mosaic expression of FMRP. [ABSTRACT FROM AUTHOR]

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 UP states in the primary somatosensory cortex are 38 – 67% longer in Fmr1 KO slices.In vivo, UP states 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 by the group 1 glutamate metabotropic receptor, mGluR5, contributes to the longer UP states. Genetic reduction or pharmacological blockade of mGluR5 rescuesthe prolonged UP state phenotype. Our results reveal 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. [ABSTRACT FROM AUTHOR]