All ETDs from UAB

Advisory Committee Chair

Linda Overstreet-Wadiche

Advisory Committee Members

Jacques Wadiche

Robin Lester

Lori L McMahon

Candace Floyd

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the central nervous system of adult mammals, new neurons are produced throughout life in at least two regions, the subventricular zone and dentate gyrus of the hippocampus. New neurons in the SVZ migrate via the rostral migratory stream and eventually participate in adaptive olfactory processes. In the dentate gyrus, a variety of physiological functions for continued addition of neurons have been proposed, but its role in normal or pathological conditions remains largely unclear. Neurogenesis in the dentate gyrus consists of the stepwise process of generating fully functional granule cells (GCs) from adult neural stem cells. Regulation of neurogenesis can occur at multiple stages by a wide range of physiological or pathological stimuli. Although many factors can influence the differentiation, maturation, and integration of newborn neurons, considerable evidence suggests γ-aminobutyric acid (GABA) signaling is a key regulator. Newborn neurons initially receive synaptic input that is exclusively GABAergic, and normal maturation and synaptic integration is profoundly disrupted when GABA signaling is altered. Hippocampal interneurons are a diverse population of GABA-releasing cells that serve specific inhibitory functions and modulate local circuitry. In the following work, I demonstrate that newborn neurons of the dentate gyrus receive GABAA receptor-mediated input with particularly slow kinetics that result from dedicated presynaptic inputs that also generate slow responses in mature GCs. This characteristically slow GABA signaling in newborn GCs arises from a unique subset of late-spiking hippocampal interneurons of the neurogliaform (NG) cell family. During synchronous activity in the dentate network, late-spiking cells provide robust depolarization to newborn cells while inhibiting other interneurons. Collectively, these data suggest that late-spiking interneurons coordinate local circuitry among new and preexisting GCs, and are poised to manipulate activity-dependent GABAergic regulation of neurogenesis.

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