Understanding how brain function emerges through the assembly of specific neuronal circuits is one of the main challenges in neuroscience. In the cerebral cortex, excitatory glutamatergic pyramidal cells and inhibitory interneurons constitute the main cellular elements of neuronal circuits. Interneuron deficits seem to underlie a variety of neurodevelopmental and psychiatric disorders in humans, but our current knowledge of the mechanisms controlling their precise integration into cortical circuits remains very limited. I aim to determine the mechanisms mediating the allocation of interneurons born in the caudal ganglionic eminence (CGE) into circuits composed of pyramidal neurons and interneurons in the cerebral cortex. The first goal of this project is to distinguish whether pyramidal cells or medial ganglionic eminence (MGE) interneurons influence the allocation of CGE interneurons in the superficial layers of the cortex. To this end, I will use a set of transgenic mouse models to specifically disrupt the normal lamination of pyramidal cells or MGE interneurons in the superficial or deep layers of the cortex and evaluate its effect on the allocation of CGE interneurons. Next, I will identify genes encoding transmembrane or secreted proteins responsible for the proper laminar allocation of CGE interneurons. This will be done both via a candidate-based approach and an unbiased screen involving fluorescence-activated cell sorting and RNA sequencing, followed by differential expression analysis. Functional analysis of candidate genes will be assessed via gain and loss of function experiments using in utero electroporation or retroviral infection prior to mutant mouse analysis. Together, these experiments will allow the dissection of the mechanisms underlying the precise integration of CGE interneurons into cortical circuits and contribute to our understanding of the etiology of several neurodevelopmental and psychiatric disorders.
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