ATR regulates neuronal activity by modulating presynaptic firing

Murat Kirtay, Josefine Sell, Christian Marx, Holger Haselmann, Mihai Ceanga, Zhong-Wei Zhou, Vahid Rahmati, Joanna Kirkpatrick, Katrin Buder, Paulius Grigaravicius, Alessandro Ori, Christian Geis () and Zhao-Qi Wang ()
Additional contact information
Murat Kirtay: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Josefine Sell: Jena University Hospital
Christian Marx: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Holger Haselmann: Jena University Hospital
Mihai Ceanga: Jena University Hospital
Zhong-Wei Zhou: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Vahid Rahmati: Jena University Hospital
Joanna Kirkpatrick: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Katrin Buder: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Paulius Grigaravicius: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Alessandro Ori: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Christian Geis: Jena University Hospital
Zhao-Qi Wang: Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Ataxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24217-2

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DOI: 10.1038/s41467-021-24217-2

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