Editors' ChoiceNeuroscience

Synaptic Activity of ATM and ATR

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Science Signaling  12 Jan 2010:
Vol. 3, Issue 104, pp. ec13
DOI: 10.1126/scisignal.3104ec13

ATM and ATR are related kinases that are best known for their roles in the DNA damage response. ATM deficiency is the cause of ataxia-telangiectasia, a disease that is associated with increased susceptibility to cancer, which can be attributed to the defects in responding to DNA damage, and various neurological symptoms, which are more difficult to attribute to a defective DNA damage response. To gain insight into the neuronal functions of ATM and ATR, Li et al. examined these kinases in neurons and brains of wild-type mice and mice deficient in ATM (Atmtm1Awb). They found that both kinases were present in the cytosol, as well as the nucleus, of cells from brain preparations, primary neuronal cultures, and a neuronal cell line. Furthermore, synaptosomal preparations contained both kinases. Coimmunoprecipitation and immunofluorescence studies showed that ATR and ATM interacted with synaptic vesicle proteins. ATR and ATM appeared to be part of a synaptic vesicle complex that contained synaptobrevin (also known as VAMP2) and synapsin-1. Western blotting with site-specific antibodies and site-directed mutagenesis revealed that synaptobrevin and synapsin-1 were phosphorylated at sites matching consensus phosphorylation sites for ATM or ATR. In brains from the Atmtm1Awb mice or in primary neuronal cultures in which ATM was knocked down, phosphorylation of synapsin-1 at the ATM/ATR consensus site was reduced, whereas synaptobrevin phosphorylation at its ATM/ATR site was not affected. Instead, knockdown of ATR in primary neuronal cultures reduced synaptobrevin phosphorylation. Knockdown of ATM disrupted the interaction between synapsin-1 and synaptobrevin in cultured neurons. Functionally, hippocampal slices from Atmtm1Awb mice showed reduced long-term potentiation at the Schaffer collateral-CA1 synapse, and cultured neurons from these mice showed a reduction in spontaneous vesicle release (as measured by release of FM4-64 dye after uptake). Thus, cytoplasmic ATM and ATR appear to serve in the regulation of synaptic vesicle release, which may contribute to the neurological symptoms of ataxia-telangiectasia.

J. Li, Y. R. Han, M. R. Plummer, K. Herrup, Cytoplasmic ATM in neurons modulates synaptic function. Current Biol. 19, 2091–2096 (2009). [PubMed]

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