All ETDs from UAB

Advisory Committee Chair

Lynn E Dobrunz

Advisory Committee Members

Rita M Cowell

John J Hablitz

Adrienne C Lahti

Lori L McMahon

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Genetic deletion of the transcriptional coactivator PGC-1α leads to transcriptional dysregulation in interneurons, and transcriptional dysregulation in interneurons lead to changes in hippocampal synaptic transmission and circuit function. Hippocampal circuit activity and synaptic transmission alterations have implications for symptoms of cognitive impairment in neurological disorders like schizophrenia. Modulation of dopamine receptor activity through pharmacologic application of haloperidol and the specific dopamine D4 receptor antagonist L-745,870 in PGC-1α-/- mice leads to altered effects on inhibitory/excitatory synaptic transmission balance, circuit function, and innate hippocampal dependent nesting behavior. These are key aspects underlying hippocampus dependent cognitive impairment. Specifically, bath application of haloperidol restores circuit function in the CA3 region of the hippocampus of PGC-1α-/- mice. L-745,870 administered to hippocampal slices restores basal synaptic transmission which enhances output from CA1 pyramidal cells by modulating inhibitory synaptic transmission presynaptically. Blockade of D4 receptors also restores kainate induced gamma oscillations and innate hippocampal dependent nesting behavior indicative of an effect on hippocampal circuit activity and activities of daily living. The key concepts uncovered in this research are 1) a link between the GABAergic system of the hippocampus and the dopamine system in PGC-1α-/- mice, 2) identification of the involvement of the D4 receptor in the enhanced inhibitory synaptic transmission and the resulting circuit and behavioral changes in PGC-1α-/- mice, and 3) the identification of a presynaptic mechanism of D4 receptor activation on hippocampal synaptic transmission, circuit function, and behavior. The results of this study have implications for the development of alternate pharmacotherapeutics to treat symptoms of cognitive impairment due to transcriptional dysregulation in interneurons of the hippocampus.

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