All ETDs from UAB

Advisory Committee Chair

Lucas-Pozzo-Miller

Advisory Committee Members

John J Hablitz

Lori L McMahon

Alan K Percy

Scott M Wilson

Document Type

Dissertation

Date of Award

2007

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Mutations in the transcriptional repressor MeCP2 cause Rett Syndrome (RTT), a mental retardation disease associated with reduced dendritic architecture of cortical pyramidal neurons, in addition to a decrease in the number of dendritic spines. I present the first quantification analysis of spine density in postmortem human brain tissue, demonstrating that hippocampal CA1 pyramidal neurons have reduced spine densities in RTT patients throughout their lives. One gene that MeCP2 regulates is BDNF, an important developmental factor that modulates synaptic transmission and plasticity, as well as spine formation and maturation. In immature cultured hippocampal neurons, cell-autonomous expression of BDNF accelerates the differentiation and growth of dendrites and axons. In hippocampal slice cultures, BDNF increases the number of dendritic spines and modulates their morphology towards more mature shaped spines. However, fine-tuned BDNF expression is critical for spine development, as BDNF overexpression in hippocampal pyramidal neurons is associated with spine regression and instability. Since BDNF is a critical player in dendritic and axonal development, I examined the influence of MeCP2 expression on neuronal differentiation and dendritic spine maintenance. The knockdown of MeCP2 in cultured hippocampal neurons and slices reduced dendritic length and number of mature-shaped spines. The overexpression of wildtype MeCP2 causes an increase in neurite outgrowth in neuronal cultures, but negatively regulates spine density 48hrs after overexpression in slice cultures. Consistent with the neuropathology observed in RTT paiii tients, overexpression of RTT-associated MeCP2 mutations diminished dendritic development and spine density. In immature cultured neurons, I show that BDNF reverts the dendritic atrophy caused by the knockdown of MeCP2 or the overexpression of MeCP2 mutations. These studies demonstrate the need of future research to expand the role of BDNF in the neuropathology of RTT, emphasizing how BDNF is modulated and released in relation to the expression of MeCP2.

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