| First Author | Kirtay M | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 4067 |
| PubMed ID | 34210973 | Mgi Jnum | J:326999 |
| Mgi Id | MGI:6725601 | Doi | 10.1038/s41467-021-24217-2 |
| Citation | Kirtay M, et al. (2021) ATR regulates neuronal activity by modulating presynaptic firing. Nat Commun 12(1):4067 |
| abstractText | 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. |
