An Examination of the Mechanisms of Neocortical Network Excitability in a Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS) is the most common heritable form of mental retardation. FXS is caused by loss of function mutations in the product of the Fmr1 gene, the Fragile X Mental Retardation Protein (FMRP). Many FXS patients display symptoms that are indicative of hyperexcitable circuitry, including epilepsy, bursting patterns in their EEG, and sensory hypersensitivity. Similarly, the mouse model of FXS, the Fmr1 KO mouse, displays a propensity for audiogenic seizures and altered sensory processing, recapitulating many of the symptoms observed in human patients. An imbalance in excitation to inhibition ratio is thought to underlie many autism spectrum disorders. The hyperexcitability in the Fmr1 KO may reflect a shift in E/I balance. However, despite the evidence for hyperexcitability, no studies have previously examined basal circuit function in the Fmr1 KO.

In this study, I report that neocortical networks are hyperexcitable in the Fmr1 KO. This hyperexcitability is manifest as prolonged persistent activity states, or UP states. UP states are cyclic periods of depolarization that occur synchronously throughout local neocortical neurons. UP states arise from local recurrent connections and are regulated by intrinsic neuronal properties. As such, measurement of UP states provides insight into overall circuit properties.

Furthermore, I observe that the increase in UP state duration in the Fmr1 KO is intrinsic to neocortical excitatory neurons. Deletion of FMRP in layer 4 or layers 5 and 6 fractionally increases UP state duration, suggesting that the hyperexcitability does not arise from one particular neuronal subtype, but rather all neurons partially contribute to the network hyperexcitation. Disruption of mGluR5 interactions with the scaffolding protein Homer, which results in consitituive mGluR5 signaling, is sufficient to prolong UP states. Futhermore, restoration of Homer-mGluR complexes in the Fmr1 KO reduces UP state duration to wildtype levels. Pharmacological or genetic reduction of metabotropic glutamate receptor 5 (mGluR5) signaling reduces UP state duration in the Fmr1 KO to normal levels, suggesting a potential therapy for Fragile X patients. These data characterize the novel phenotype of hyperexcitable cortical circuitry in the Fmr1 KO. In addition, this study provides support for an mGluR-Homer dependent mechanism underlying the network hyperexcitability that may be useful in developing additional treatments for FXS. [Keywords: Fragile X Syndrome, FMRP, UP state, mGluR5, Neocortex, network, hyperexcitability, Homer]