Activity-Dependent Circuit Integration of Somatostatin Interneuron Subtypes in the Developing Neocortex - Project Summary The mammalian cortex consists of many transcriptionally distinct neuronal cell types connected in intricate circuits. Much work has shown that risk genes associated with developmental disorders such as schizophrenia, autism spectrum disorder, epilepsy and intellectual disorder encode synaptic proteins enriched in cortical interneurons (cIN). However, not much is known about how cINs integrate into cortical circuits during development. Thus, understanding how this process occurs will allow us to understand how the cortex develops in both healthy and pathophysiological states. Early studies used electrophysiological and morphological analysis to define four cardinal classes of interneurons with varying levels of heterogeneity within those classes. More recent advances in single-cell, spatial and combinatorial transcriptomic techniques have uncovered an even wider breadth of diversity. The somatostatin (SST) class is of particular interest because they are enriched in infragranular layers of the cortex yet display highly specialized targeting of pyramidal neuron dendrites. This requires them to extend their axons across multiple layers to connect to their synaptic partners. Their role in routing feedback inhibition suggests that they influence dendritic computations in pyramidal neurons (PNs) by regulating information flow. Proper maturation of cortex requires SST interneurons to successfully integrate into cortical circuits, yet the cellular and subcellular specificity in efferent targeting of SST interneuron subtypes is currently unknown. The molecular and genetic tools that have been generated and validated in our lab has positioned me to utilize slice physiology, immunohistochemistry and viral labeling methods to not only investigate the specificity in SST subtype connectivity, but also to evaluate how this arises in development. As yet, it is unknown whether SST efferent targeting is initially specific or refined across development. Furthermore, recent work has shown that SST interneurons transiently target PV interneurons during development and that this is instructive to the formation of PV microcircuits. Thus, it is likely that SST circuit integration is dynamic across development. Therefore, I also aim to determine how SST efferent specificity arises and whether transient connectivity’s exist across development. However, the study of the assembly of cortical microcircuits must consider developmental activity, as much work has uncovered the dependance of interneuron maturation and circuit integration on intrinsic activity. Given the incredible advances in transcriptomics clarifying the diversity within the SST interneuron class, and the viral and transgenic tools that now exist to target, label and manipulate specific cortical neuron subtypes, we are now well positioned to assess the role of developmental intrinsic activity on synaptic specificity. Thus, in my final set of experiments, I will determine the role of developmental activity in SST circuit integration and the critical period for this activity in proper synaptic maturation of SST subtype-specific microcircuits. The project that I have proposed is designed to fill the gap in knowledge of how SST subtypes integrate and function in specific microcircuits and lay the foundation for future mechanistic studies.
