In the mammalian cerebral cortex, inhibitory interneurons sculpt the flow of excitatory information. This complex task is carried out by a wide variety of interneuron subtypes which play distinct roles in cortical function. However, the developmental origins of interneuron diversity is largely unknown. Two major classes of interneurons, parvalbumin (PV)+ fast-spiking basket cells and somatostatin (SST)+ Martinotti cells, are both derived from a common embryonic origin yet differentiate into highly specialized cell types. Mechanisms that control the diversification of these cell types and specify their integration into their respective circuits are not well understood. Increasing evidence suggests that this process depends not only on initial genetic determinants of cell fate, but also activity-dependent signals once the interneurons invade the cortex and begin for form synapses. One candidate signaling factor to mediate cortical interneuron maturation and synaptic integration is brain-derived neurotrophic factor (BDNF), which is a neurotrophin critical for the development of several cells types and has been shown to regulate inhibition in the developing cortex. However, the contribution of the BDNF high-affinity receptor TrkB to interneuron development has never been tested. Strikingly, BDNF also seems to influence the timing of visual critical period plasticity, which has long been hypothesized to be controlled by the maturation of inhibition in visual cortex. Despite substantial evidence supporting this hypothesis, the contributions of distinct subtypes of interneurons to the visual critical period have not been fully explored. Furthermore, cell-autonomous signaling pathways that link interneuron maturation with the developing visual network to control the precise timing of the visual critical period are not known. This project aims to address these questions by 1) dissecting the requirement of the TrkB receptor in PV and SST interneuron cellular and synaptic maturation and 2) assessing the contribution of BDNF signaling onto PV and/or SST interneurons for the onset of the visual critical period. These goals will be accomplished through a combination of longitudinal fate-mapping, molecular profiling, and electrophysiology both in vitro and in vivo. This effort will provide insight into activity-dependent determinants of interneuron function and dissect the roles of two major inhibitory subtypes in the onset of the critical period through a novel signaling pathway.
Inhibitory neuron dysfunction has been implicated in the etiology of many psychiatric neurodevelopmental disorders, such as autism spectrum disorder (ASD), schizophrenia, and epilepsy. Improving our understanding of how specific activity-dependent signaling pathways contribute to inhibitory neuron development and circuit integration can help us better define of the underlying pathological mechanisms of neurological and neurodevelopmental disorders. This project will produce invaluable insight into how genetic disruptions in these cell types affect brain circuit development and function, and will potentially identify molecular targets that will be useful for the development of tools and therapeutic approaches to successfully treat these disorders.
