All ETDs from UAB

Advisory Committee Chair

Linda Overstreet-Wadiche

Advisory Committee Members

Rita Cowell

John Hablitz

Erik Roberson

Jacques Wadiche

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The dentate gyrus (DG) contains neural stem cells that continually generate new neurons throughout life. The contribution of adult neurogenesis to hippocampal function is not well understood, but ablation or silencing of adult-generated neurons in the DG disrupts learning and memory, and neurogenesis is altered in many pathologies associated with impaired cognition including Alzheimer's Disease, epilepsy, and schizophrenia. Neurogenesis in the DG is a stepwise process in which neural stem cells leave the cell cycle and undergo an approximately two month long maturation process to form fully functional dentate granule cells (GCs) that are indistinguishable from those formed during development. The newly formed GCs incorporate into the preexisting network, providing a unique form of neural plasticity. However, only a fraction of newly generated GCs survive, while most undergo apoptotic cell death within the first few weeks of maturation. The fate of these cells can be influenced by an animal's experience. For example, exposing rodents to environmental enrichment (EE) increases the survival rate of adult-generated GCs, but experience can only promote survival during an early maturation stage termed the "critical period." Both GABAergic and glutamatergic mechanisms have been implicated in the survival of newborn GCs, suggesting that synaptic input is important for fate-determination. Yet little is known about synaptic signaling at this stage. This work demonstrates that the POMC-GFP transgenic mouse model labels a population of newborn GCs in the critical period for survival. In addition to slow GABAergic synaptic inputs, these newborn GCs have glutamatergic transmission mediated solely by NMDA receptors (NMDARs), and we show that GABA synaptic activity provides the depolarization necessary for rapid NMDAR-dependent AMPA receptor (AMPAR) incorporation at the first silent synapses in an activity-dependent manner. Furthermore, we show that mossy cells, part of the local feedback circuitry, provide the earliest glutamatergic inputs to critical period GCs. Together these data demonstrate that neuronal activity promotes synaptic integration of adult-generated GCs, thereby, driving experience-dependent circuit formation.

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