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theses

Ataxia-telangiectasia (A-T) is a devastating childhood disorder caused by mutation of the ataxia-telangiectasia mutated gene (ATM) which encodes a member of the PI3 kinase family. In most cells, ATM is localized in the nucleus and is involved in DNA damage repair. In neurons, however, a substantial fraction of ATM is cytoplasmic, and the function of this cytoplasmic pool is poorly understood and not well studied. Since likely binding partners of ATM include the molecules synapsin-I and VAMP2, we examined the possibility that cytoplasmic ATM is a regulator of synaptic plasticity. FM4-64 dye tracing experiment showed a deficit of spontaneous vesicle releasing in ATM deficient cells. Hippocampal slice recordings revealed that Shaffer collateral long-term potentiation (LTP) in homozygous Atmtm1Awb mice was significantly reduced comparing to wild-type controls. In Atmtm1Awb mutant mice, ATM protein is still made, but is a novel, catalytically less active, splice mutant product. By comparison in Atmtm1Bal mutant mice in which the protein is not made, short-term plasticity such as synaptic fatigue and paired-pulse facilitation were compromised, whereas LTP was less affected. Binding studies show that cytoplasmic ATM serves as a scaffold that brings together ATR, synapsin-I and VAMP2. This observation suggests that cytoplasmic ATM in the Atmtm1Awb mice may be acting to disable the complex, whereas the simple absence of ATM is less disruptive. The next stage of this work will focus on understanding the mechanism of how cytoplasmic ATM is involved in synaptic function.

ETD_4684

Ph.D.

Includes bibliographical references

Includes vita

by Yu Ray Han

http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000068874

doi:10.7282/T3DR2T3F

ETD doctoral

The author owns the copyright to this work.