Neurodevelopmental disorders such as autism produce significant emotional, physical, and economic consequences for affected individuals and their families. Autism spectrum disorders (ASDs) affect approximately 1% of the worldwide population and are associated with cognitive deficits in perception, social interaction, and communication, all functions served by the cerebral cortex. While the cellular mechanisms underlying ASDs remain unclear, recent evidence suggests disruption of GABAergic inhibitory interneurons (INs) may contribute to abnormal development and function of cortical circuits. Genetic studies of ASD patients have identified several candidate genes including MeCP2, a gene strongly associated with Rett Syndrome (RTT), and IN-specific deletion of MeCP2 produces many ASD-like phenotypes. However, little is known about the specific cellular, synaptic, and circuit consequences of IN dysregulation. To address this question, we propose to use a mouse model in which MeCP2 is deleted in a distinct subpopulation of dendrite-targeting GABAergic INs, focusing on the mouse visual system. Altered sensory processing is a hallmark of ASDs, and the wealth of knowledge on the normal function of the visual cortex will provide critical context for interpreting the cellular mechanisms underlying observed circuit and behavioral abnormalities. Specifically, we will test the following three hypotheses: (1) MeCP2 expression in somatostatin-expressing (SOM) INs regulates cortical neuronal morphology and connectivity. (2) SOM-IN dysregulation contributes to cortical circuit dysfunction in the MeCP2 model. (3) SOM-IN-specific MeCP2 deletion impairs visual perception. We will combine electrophysiological and anatomical analyses ex vivo with high-density neuronal recordings and behavioral analyses in vivo. This approach will allow us to generate novel insights into the links between structural and synaptic dysregulation and dysfunction of neural circuits in an established model of neurodevelopmental disorders.
GABAergic interneurons (INs) play key roles in the normal development and maintenance of neocortical circuits. This proposal will determine how distinct genetically targeted IN populations contribute to cortical dysfunction in a mouse model of Rett Syndrome (RTT). We expect our findings to provide important insights into the cellular underpinnings of this disorder and suggest new avenues for therapeutic intervention.
|Cardin, Jessica A (2018) Inhibitory Interneurons Regulate Temporal Precision and Correlations in Cortical Circuits. Trends Neurosci 41:689-700|