All ETDs from UAB

Advisory Committee Chair

John J Hablitz

Advisory Committee Members

Rita Cowell

Kazutoshi Nakazawa

Lucas Pozzo-Miller

Linda Wadiche

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The excitatory glutamatergic output of the cerebral neocortex is tightly regulated by the release of the inhibitory neurotransmitter GABA from cortical interneurons (INs). Once viewed as a largely homogenous population, recent studies have revealed that cortical INs display a diverse range of biochemical, anatomical and physiological properties. In this work we sought to determine if differences in the physiology and connectivity patterns of identified cortical IN populations enable them to differentially contribute to network activity. Specifically, we investigated the contribution of discrete L2/3 IN groups to the generation of aberrant cortical synchrony, and the influence of HCN channels on information processing via modulation of the excitability of layer I (L1) INs. In a model of epilepsy which induces cortical GABAergic hypersynchrony, we found that biochemically identified IN subclasses differentially contribute to the generation of epileptiform activity. Specifically, activation of parvalbumin (PV)-expressing INs was found to be critical for the generation of epileptiform bursts, whereas inhibition of somatostatin (SOM) or vasointestinal peptide (VIP)-expressing INs only marginally reduced epileptiform activity. Furthermore, activation of either PV or SOM-expressing was sufficient to generate epileptiform activity, whereas activation of VIP INs was not. Together, these results indicate cell type-specific contributions of INs to network activity, potentially facilitated by their distinct patterns of synaptic connectivity. In examining the role of HCN channels in modulating the excitability cortical L1 INs, we were able to identify three physiologically distinct populations of mature L1 INs, each exhibiting unique effects of Ih on their intrinsic and synaptic excitability. In addition, we found Ih to be developmentally regulated in these populations, with inverse patterns of effects being observed in different groups. Considered with previous data concerning L1 IN control of cortical excitation, the identified patterns of HCN-mediated excitability modulation appear to serve complementary roles in tempering cortical activity in an age-dependent manner. Overall, these results highlight the functional diversity of cortical INs and identify key traits underlying differential neuronal function.

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