Two Tales of Cortical GABAergic System Development

Abstract

γ-Aminobutyric acid (GABA) type A receptors (GABARs) are ligand-gated Cl- channels that mediate the bulk of inhibitory neurotransmission in the mature brain. Disruptions in GABAergic signals underlie a significant portion of neurological and neurodevelopmental disorders, and GABARs are the targets of many drugs. In contrast to adulthood, GABAergic signaling can act in excitatory capacity during development, playing important roles in developmental processes like neuronal migration and circuit formation. In this dissertation, I and co-authors focus on progressive changes in GABAR composition and late expression of K-Cl transporter KCC2 that alter GABAergic signals during development to fit unique developmental functions. In the second chapter, we investigate the role of KCC2 in development of cortical GABAergic interneurons (INs) by creating mice with pan-IN and IN subtype-specific conditional knockouts of KCC2. We found that while some INs express KCC2 earliest among cortical neurons, loss of KCC2 did not impact IN migration as predicted by KCC2 overexpression studies, but did affect IN distribution at late postnatal timepoints in an IN subtype-specific manner, particularly showing loss of parvalbumin+ (PV+) INs. Additionally, loss of KCC2 in INs had a pronounced mouse phenotype similar to a full KCC2b knockout, characterized by failure to thrive and spontaneous seizure activity. However, this phenotype was not exhibited by mice with late postnatal loss of KCC2 in PV+ INs. In the third chapter, we undertake a comprehensive investigation of progressive changes in GABAR subunit and KCC2 expression throughout cortical development. We found expression patterns that corroborate previously published data, but offer considerably greater resolution of temporal and layer-specific changes in expression. These studies support the hypothesis that changes in GABAR composition and KCC2 expression accompany cortical development, and underlie a transition from GABAergic developmental signals to mature synaptic neurotransmission.