This grant proposes to determine whether binocular activation of fast-spiking inhibitory neurons is upstream of the maturation of inhibitory output onto pyramids, and whether maturation of inhibition directs wiring of excitatory connections within the binocular zone of visual cortex. Our studies utilize 2-photon visually guided loose cell attached and whole cell voltage clamp recordings of pyramidal neurons and parvalbumin-expressing interneurons. Manipulations of the Neuregulin/ErbB4 signaling pathway are used to accelerate or impair the maturation specifically of parvalbumin- expressing interneurons to determine whether this inhibition guides the appropriate maturation of excitatory input onto pyramidal neurons in vivo. The Neuregulin/ErbB4 signaling pathway is implicated in schizophrenia, a disease thought to result from a developmental impairment in the recruitment of inhibition. Results from the proposed studies will determine the interrelationship between the recruitment of a specific class of inhibitory neurons and the establishment of normal excitatory cortical circuitry and responsiveness. These results will identify developmental epochs of highest sensitivity to inhibitory maturation, providing important new information with strong relevance to schizophrenia research.
This work will provide fundamental insights into mechanisms that control the recruitment of inhibition in developing cortex and will determine whether maturation of inhibition directs wiring of excitatory connections in cortex. Emphasis is placed on examining the role of Neuregulin/ErbB4 signaling in this process - both schizophrenia susceptibility genes. Our data will provide insight into the development of schizophrenia, identifying developmental stages with the highest impact for intervention.
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