A key question in developmental neurobiology involves how intrinsic lineage- specifying gene programs integrate with sensory-driven neuronal activity to mature neural circuits. GABAergic interneurons provide a particularly facile system in which to address this issue. Initial specification of interneurons occurs during embryonic growth through expression of specific regulatory transcription factors. Interneurons undergo further activity-dependent maturation during early postnatal development to guide their migration to distinct regions of the cortex and shape their dendritic complexity and inhibitory connections. It is unknown whether neuronal activity regulates this postnatal maturation by activating unique sets of genetic regulatory elements, such as enhancers, that promote sustained alterations to the gene expression programs of interneurons. Alternatively, the selection of enhancers that drive gene programs critical for postnatal maturation may instead be driven by cell-type-specific transcription factors intrinsic to a particular class of interneuron. The proposed studies will clarify the roles of cell-type-specific and activity-dependent transcription factors in regulating enhancer selection during postnatal development.
Specific Aim 1 will use an unbiased approach exploiting natural genetic variation between different strains of mice to determine the effect of disrupting transcription factor binding sites on selection of enhancers in Parvalbumin-expressing interneurons.
Specific Aim 2 will assess the impact of neuronal activity in shaping the landscape of active enhancers in interneurons during the course of postnatal development. The proposed studies will identify lineage-specific and activity-dependent transcription factors critical for enhancer selection in interneurons, providing further insight into the regulation of interneuron specification, maturation, and integration into neural circuits. Greater understanding of these processes will inform the study of human neurodevelopmental disorders displaying aberrant interneuron development and function, including schizophrenia, epilepsy, and autism spectrum disorders.
Aberrant interneuron development is implicated in a number of neurological and psychiatric disorders, including schizophrenia, epilepsy, and autism spectrum disorders. Understanding the regulation of gene expression programs that specify interneurons and promote their maturation during early postnatal life is critical to understanding the etiology of these disorders. The proposed studies will define the contributions of cell-intrinsic factors and sensory-driven stimuli to the function of genetic regulatory elements in interneurons, providing further insight into the control of interneuron specification during postnatal development.