All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Rita Cowell

Lynn Dobrunz

Yogesh Dwivedi

Richard Shelton

Linda Wadiche

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Major Depressive Disorder (MDD) in a common mental disorder that can impair cognitive functioning and negatively impact hippocampus. While several pharmacological treatments are currently available for MDD, most target the monoamine system, providing little variety in approaching treatment. Additionally, a large percentage of people with MDD have an inadequate response to this drug class, leaving them with little optimism of a full functional recovery. Recently, low-dose ketamine, an open-channel N-methyl D-aspartate receptor (NMDAR) antagonist, produced rapid antidepressant effects in humans, including people who do not respond to monoamine-based therapies, that lasted for days. The antidepressant-like behavioral effect of ketamine is mimicked in preclinical rodent models, but unfortunately, understanding how ketamine changes brain function to initiate this response is limited. Disinhibition of pyramidal cells via decreased output of fast spiking GABAergic interneurons has been proposed as a key mechanism but has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans is unknown. To determine if clinically relevant concentrations of ketamine and other rapid antidepressants disinhibit pyramidal cells, I employed in vitro electrophysiology in acute slices of dorsal hippocampus from male Sprague-Dawley rats. Ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven excitability measured at the single cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show an increase in the excitation/inhibition (E/I) balance, which supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. Extending the functional investigation of ketamine into the initial hours (hrs) after treatment, we observed enhanced long-term potentiation (LTP), or activity-dependent plasticity, at CA3-CA1 synapses. Importantly, this timeframe correlates to that during which symptoms are first improved in patients, and is an additional functional change in synaptic circuits that could contribute to the antidepressant effects. Furthermore, this effect of ketamine may potentially negate the synaptic deficits observed in animals bred for depression-like phenotypes. Together, these experiments suggest a role of early functional changes in hippocampal circuits in the effects of rapid antidepressants.

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