Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits
Renee J. Tamming,
Vanessa Dumeaux,
Yan Jiang,
Sarfraz Shafiq,
Luana Langlois,
Jacob Ellegood,
Lily R. Qiu,
Jason P. Lerch,
Nathalie G. Bérubé
Affiliations
Renee J. Tamming
Children’s Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Biochemistry, Western University, London, ON, Canada
Vanessa Dumeaux
Department of Paediatrics, Western University, London, ON, Canada; PERFORM Centre, Concordia University, Montreal, QC, Canada
Yan Jiang
Children’s Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada
Sarfraz Shafiq
Children’s Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada
Luana Langlois
Children’s Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada
Jacob Ellegood
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
Lily R. Qiu
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK
Jason P. Lerch
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK
Nathalie G. Bérubé
Children’s Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Corresponding author
Summary: ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the suppressive histone mark H3K27me3 is significantly reduced upon the loss of ATRX. We conclude that the ablation of ATRX in excitatory forebrain neurons leads to sexually dimorphic effects on miR-137 expression and on spatial memory, identifying a potential therapeutic target for neurological defects caused by ATRX dysfunction.
