Abstract

GABAA receptors (GABAARs) are the primary inhibitory neurotransmitter receptors in the central nervous system. A rich diversity of receptor subtypes are produced by the combination of various GABA receptor subunits into a heteropentameric chloride channel. Inhibitory signaling through GABAARs occurs on timescales ranging from fast synaptic events lasting milliseconds to tonically active receptors providing standing inhibitory tone. GABAARs are modulated by many clinically important drugs including anesthetic, hypnotic, anxiolytic, and antidepressant agents. Of note, GABAARs are modulated by neurosteroids, which have recently been developed as novel therapeutic agents for psychiatric disease. The synchronized activation of GABAARs through coordinated activity of GABAergic interneurons is important for organizing large populations of principal cells into synchronized network activity. Both the manipulation of GABA releasing interneuron activity and modulation of GABAARs can alter the network activity observed as oscillatory signals in the brain. This thesis investigated both of these means of network perturbation to characterize modulation of neural oscillations by the neurosteroid allopregnanolone (AlloP) a positive GABAAR modulator, and to probe the function of δ subunit containing GABAARs in parvalbumin positive (PV+) interneurons with respect to their role in supporting coordinated network activity. First I characterized the EEG response to AlloP in comparison to other GABAAR positive modulators and the rapid antidepressant ketamine in attempt to differentiate AlloP effects from other GABA modulators and identify potential common signatures of rapid antidepressants. I found that non-sedative doses of AlloP most closely resembled the actions of pentobarbital a non-selective GABAAR positive modulator, and failed to identify any significant overlap between actions of AlloP and ketamine among any analyzed EEG parameters. This suggests that rapid antidepressants with different molecular targets maintain separate actions when measured across larger scales of neural activity. Next we considered whether the unique α1/δ GABAAR subunit partnerships found on PV+ interneurons could serve as a disinhbitory substrate for neurosteroids. We found that hippocampal PV+ interneurons exhibited very little sensitivity to modulation by AlloP, and that mice lacking Gabrd in PV+ interneurons (PV-δcKO) retained EEG responses to non-sedative AlloP doses similar to wild type animals. Finally, we sought to determine how inhibition through δ-subunit containing receptors in PV+ interneurons shape their role to support coordinated network activity. We found that PV-δcKO mice had altered EEG spectra, notably increased power of lower frequency activities during sleep. Additionally, we identified the emergence of high amplitude phasic bursts of activity prominently detected in frontal cortical areas that were mitigated upon viral reintroduction of Gabrd to PV+ interneurons. These studies expand our knowledge of neurosteroid modulation of mesoscale activities and highlight an importance of GABA signaling through δ subunit containing receptors on PV+ interneurons for maintaining integrity of oscillatory activity in the brain.

Committee Chair

Steven Mennerick

Committee Members

Adam Kepecs; Alexxai Kravitz; Jordan McCall; Marco Pignatelli

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-21-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-9427-638X

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