Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism

Fu-Sun Lo, Reha S. Erzurumlu

Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The humanMetgene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation ofMetin excitatory cortical neurons in mice (Emx1 cre /Met flox mice) yields a phenotype in which significantly decreased GABAAreceptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactiveMetgene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAAreceptors in the somatosensory cortex ofEmx1 cre /Met flox mice. In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone inMet-defective cortex. Thus, insulin resistance of GABAAreceptor-mediated response inMetmutant mice may result from desensitized insulin receptors. Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment.