The Role of Layer I Interneurons in the Activity-Dependent Assembly of the Somatosensory Cortex

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PROJECT SUMMARY/ABSTRACT Individuals with Autism Spectrum Disorders (ASD) and related neurodevelopmental diseases exhibit diverse manifestations of the stereotyped socioemotional limitations of these conditions. Prominently, deficits in the processing and interpreting of sensory inputs are consistently observed. Foundational studies implicate inhibitory interneuron dysfunction in the pathogenesis of ASD as well as the role of select interneuron subtypes in coordinating organization of sensory processing cortical areas. We hypothesize that sensory input to defined subtypes of inhibitory interneurons at early developmental stages is necessary to recruit genetic programs mediating the emergence of correctly patterned sensory maps. To test this hypothesis, we will demonstrate the local circuitry of a molecularly-defined subtype of superficial interneurons, which underlies their coordinating role in sensory cortical assembly, using a combination of immunohistochemical and electrophysiologic profiling. We will show that sensory deprivation though genetic ablation of a high-risk ASD gene in these interneurons alters their transcriptional programs in an activity- dependent manner. Finally, we will implicate the sensory-sensitive expression of an emerging subtype-defining gene in these interneurons as necessary and sufficient for driving their role in sharpening sensory maps at neonatal stages and for consequent tactile sensing behavior in adulthood. This proposal, undertaken with the intellectual support of the Tri-Institutional research community and the guidance of a mentorship team at the nexus of neuroscience and psychiatry, will address a significant gap in understanding the intersection between genetic risk and aberrant activity-dependent sensory processing circuitry in the emergence of ASD symptomatology.