| First Author | You JC | Year | 2017 |
| Journal | Nat Med | Volume | 23 |
| Issue | 11 | Pages | 1377-1383 |
| PubMed ID | 29035369 | Mgi Jnum | J:252614 |
| Mgi Id | MGI:6103431 | Doi | 10.1038/nm.4413 |
| Citation | You JC, et al. (2017) Epigenetic suppression of hippocampal calbindin-D28k by DeltaFosB drives seizure-related cognitive deficits. Nat Med 23(11):1377-1383 |
| abstractText | The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer''s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that DeltaFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of DeltaFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of DeltaFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by DeltaFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures. |
