Date of Award

Spring 1-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Tin Tin Su

Second Advisor

Kevin R. Jones

Third Advisor

Bradley B. Olwin

Fourth Advisor

Mark Winey

Fifth Advisor

Susan L. Patterson

Abstract

Originally discovered in the peripheral nervous system, Brain Derived Neurotrophic Factor (BDNF) is a target derived trophic factor that acts retrogradely to enhance neuron survival. BDNF is the most abundant neurotrophin found in the brain and it can be expressed and secreted both pre- and post-synaptically by cortical neurons. Recent studies suggest that BDNF may mediate synaptic competition during the critical period in the visual cortex. Here we show the first evidence that a decreased level of BDNF alone is sufficient to induce competition-driven dendritic spine loss in the cortex of adult mice. We injected adeno-associated virus, carrying the gene for Cre-recombinase (AAV-Cre), into the visual cortex of mice with a floxed BDNF transgene, in order to produce isolated BDNF mutant cells. Our data demonstrates that isolated homozygous BDNF mutant neurons embedded in a wild type environment show a reduction in dendritic spine density. Additionally, isolated BDNF heterozygous neurons surrounded by wild type neurons display the same decrease in dendritic spine density. In contrast, BDNF heterozygous neurons in an environment of other BDNF heterozygous neurons did not show a similar reduction in spine density. This provides strong evidence that BDNF is an essential requirement for mediating competitive interactions that determine dendritic spine density. Furthermore, these data demonstrate that isolated BDNF mutant neurons cannot be rescued by their wild-type neighbors, indicating BDNF signals at the level of the individual neurons in the cortex. Overall, these data support a model in which the formation and/or stabilization of many cortical excitatory synapses relies upon competition for a cell-autonomous supply of BDNF.

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