Date of Award

12-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Neuroscience

Research Advisor

Stanislav S. Zakharenko, M.D. Ph.D.

Committee

Suzanne J. Baker, Ph.D. Joseph C. Callaway, Ph.D., B.A. Matthew Ennis, Ph.D., B.A. Peter J. McKinnon, Ph.D.

Keywords

Hippocampus, Long-term potentiation (LTP), Long-term depression (LTD), Pdk1, PTEN

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) -signaling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size and synaptic transmission and plasticity. Neurologic abnormalities such as autism, seizures, and ataxia are associated with inherited PTEN mutations. Yet, how PTEN loss contributes to neurologic dysfunction remains unknown. PTEN loss during early development is associated with extensive deficits in neuronal migration and substantial hypotrophy of neurons and synaptic densities. However, whether its effect on synaptic transmission and plasticity is direct or mediated by structural abnormalities remains unknown. Here we analyzed neuronal and synaptic structures and function in Pten-conditional knockout mice in which the gene was deleted from excitatory neurons during late development. Using 2-photon imaging, Golgi staining, immunohistochemistry, electron microscopy, and electrophysiologic tools, we determined that late Pten loss does not affect hippocampal development, neuronal or synaptic structure or basic synaptic transmission. However, it does cause deficits in both major forms of synaptic plasticity, long-term potentiation and long-term depression. Deletion of Pdk1, the positive regulator of the PI3K pathway, rescued Pten-mediated deficits in synaptic plasticity. These results suggest that Pten independently modulates functional and structural properties of hippocampal neurons and is directly involved in mechanisms of synaptic plasticity.

DOI

10.21007/etd.cghs.2011.0295

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