Epigenetic suppression of hippocampal calbindin-D28k by Δ FosB drives seizure-related cognitive deficits

Nature Medicine 23, 1377 (2017). doi:10.1038/nm.4413 Authors: Jason C You, Kavitha Muralidharan, Jin W Park, Iraklis Petrof, Mark S Pyfer, Brian F Corbett, John J LaFrancois, Yi Zheng, Xiaohong Zhang, Carrie A Mohila, Daniel Yoshor, Robert A Rissman, Eric J Nestler, Helen E Scharfman & Jeannie Chin 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 ΔFosB, 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 ΔFosB signaling, improves spatial memory in a mouse ...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research