Investigating the Role of ATRX in Glutamatergic Hippocampal Neurons
Abstract
Mutations in ATRX, a Snf2-type chromatin remodeler, frequently lead to intellectual disability. However, the function of ATRX within the brain in cognition and synaptic transmission are incompletely understood. The aim of this study was to investigate the role of ATRX in the adult mouse brain. While complete loss of ATRX in the embryonic mouse brain results in perinatal lethality, mosaic expression of ATRX stunted growth and perturbed circulating IGF-1 levels. Mosaic expression of ATRX also impaired adult cognition, specifically recognition memory and spatial learning and memory. However, there were confounding factors that led me to a new model in which I deleted the gene in postnatal mouse glutamatergic neurons. Magnetic resonance imaging of these mice revealed increased hippocampal CA1 and CA3 layers, and behaviour analysis indicated deficiencies in hippocampal-dependent learning and memory in the contextual fear task, Morris water maze, and paired-associate learning task. These behavioural abnormalities were not present in the female counterparts. Transmission electron microscopy of male hippocampal CA1 synapses revealed decreased number of total and docked vesicles and increased cleft width and post-synaptic density size. Hippocampal RNA-sequencing followed by sex-interaction analysis of male and female knockout transcripts highlighted potential impairments in the synaptic vesicle cycle. miR-137, a known regulator of presynaptic vesicle cycle and plasticity, was upregulated in the male knockout hippocampi but downregulated in the female knockouts. These results demonstrate sexually-dimorphic regulation of miR-137 and learning and memory by ATRX in forebrain glutamatergic neurons, indicating potential miRNA-targeting therapies for cognitive disorders by ATRX mutations.