Comparative electrophysiological analysis of αV and β3 integrin knock-out mice

Epilepsy and autism spectrum disorder have a high degree of comorbidity, likely due to shared underlying predisposing factors. Loss of αV and β3 integrin subunits have been implicated in the onset of epilepsy and autism, respectively. However, the role of the αVβ3 integrin receptor in these disorders remains unclear. Integrins are heterodimeric receptors involved in mechanotransduction between the extracellular matrix and the intracellular cytoskeleton. In the brain, β3 integrin forms heterodimers with αV integrin, regulating the synaptic localization of GluA2-containig AMPA receptors (AMPARs) and of metabotropic glutamate receptor 5 (mGluR5). We performed comparative electrophysiological analyses on two mouse models: a constitutive KO mouse for β3 integrin and a conditional KO mouse for αV integrin. To study the interplay between αVβ3 integrin and group I mGluRs, we recorded AMPAR excitatory post-synaptic currents (EPSCs) in cortical neurons of both mouse models upon pharmacological modulation of mGluR1/5. Inhibition of mGluR5 with the antagonist MPEP induced a comparable reduction of AMPAR EPSCs in Itgb3 and ItgaV KO neurons. Moreover, we explored how inhibiting mGluR5 affected AMPAR phosphorylation levels in the cortices of Itgb3 WT and Itgb3 KO mice. These results suggest a common dysfunctional mechanism of mGluR5 signaling in the absence of αVβ3 integrin, leading to the increased excitability, seizure susceptibility and social deficits observed in these mice.