Neural Mechanism for the assembly of GABAergic in the cerebral cortex

Project Summary Dysfunction of gamma-aminobutyric acid (GABA)ergic interneurons is strongly associated with neurological disorders including epilepsy, schizophrenia and autism spectrum disorders. Although recent evidence highlights bewildering subtype diversity of these neurons, the notion that developmental perturbations in subtype function cause defects in the formation of cortical circuits with lasting functional deficits has not been explored in detail. The long-term goal of this research is to uncover how early interneuron dysfunction in the developing postnatal brain leads to lasting neurological pathologies. The objective of this proposal is to reveal how the activity of specific interneuron populations during critical windows of perinatal development shape circuits underlying primary sensory-dependent behavior. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation. We will focus our studies in superficial circuits since our previous work indicates that these circuits are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at investigating the role of layer I interneuron subtypes in regulating the emergence of cortical columns (Aim 1). In addition, this project will determine the role of LI interneurons in the emergence of interhemispheric circuits. (Aim 2). Finally, we will assess how developmental defects in early LI interneuron function lead to abnormal brain activity and impaired sensory integration in the adult (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy excitatory/inhibitory balance. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how early interneuron dysfunction may lead to behavioral abnormalities frequently observed in ASD patients.