title: ATM protein is located on presynaptic vesicles and its deficit leads to failures in synaptic plasticity.
abstract: Ataxia telangiectasia is a multisystemic disorder that includes a devastating neurodegeneration phenotype. The ATM (ataxia-telangiectasia mutated) protein is well-known for its role in the DNA damage response, yet ATM is also found in association with cytoplasmic vesicular structures: endosomes and lysosomes, as well as neuronal synaptic vesicles. In keeping with this latter association, electrical stimulation of the Schaffer collateral pathway in hippocampal slices from ATM-deficient mice does not elicit normal long-term potentiation (LTP). The current study was undertaken to assess the nature of this deficit. Theta burst-induced LTP was reduced in Atm(-/-) animals, with the reduction most pronounced at burst stimuli that included 6 or greater trains. To assess whether the deficit was associated with a pre- or postsynaptic failure, we analyzed paired-pulse facilitation and found that it too was significantly reduced in Atm(-/-) mice. This indicates a deficit in presynaptic function. As further evidence that these synaptic effects of ATM deficiency were presynaptic, we used stochastic optical reconstruction microscopy. Three-dimensional reconstruction revealed that ATM is significantly more closely associated with Piccolo (a presynaptic marker) than with Homer1 (a postsynaptic marker). These results underline how, in addition to its nuclear functions, ATM plays an important functional role in the neuronal synapse where it participates in the regulation of presynaptic vesicle physiology.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey;
authors.forename: Graham
authors.initials: G
authors.lastname: Vail
authors.affiliation: Division of Life Science and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; and.
authors.forename: Aifang
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey;
authors.forename: Yu Ray
authors.initials: YR
authors.lastname: Han
authors.affiliation: Department of Physics, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Teng
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Physics, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Shengwang
authors.initials: S
authors.lastname: Du
authors.affiliation: Department of Physics, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Michael M T
authors.initials: MM
authors.lastname: Loy
authors.affiliation: Division of Life Science and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; and.
authors.forename: Karl
authors.initials: K
authors.lastname: Herrup
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey; mplummer@rci.rutgers.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Plummer
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017774:Long-Term Potentiation / Q000502:physiology*; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008853:Microscopy; D061848:Optical Imaging; D017729:Presynaptic Terminals / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: ATM; LTP; paired-pulse facilitation; presynaptic plasticity; storm super-resolution microscopy; synaptic decay