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

doi:10.1016/j.celrep.2020.107838

Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits

Cell Rep. 2020 Jun 30;31(13):107838. doi: 10.1016/j.celrep.2020.107838.

Authors

Renee J Tamming¹, Vanessa Dumeaux², Yan Jiang³, Sarfraz Shafiq⁴, Luana Langlois⁵, Jacob Ellegood⁶, Lily R Qiu⁷, Jason P Lerch⁸, Nathalie G Bérubé⁹

Affiliations

¹ Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Biochemistry, Western University, London, ON, Canada.
² Department of Paediatrics, Western University, London, ON, Canada; PERFORM Centre, Concordia University, Montreal, QC, Canada.
³ Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada.
⁴ 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.
⁵ 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.
⁶ Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK.
⁸ 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.
⁹ 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. Electronic address: nberube@uwo.ca.

Abstract

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.

Keywords: ATRX; H3K27me3; chromatin; hippocampus; intellectual disability; long-term spatial memory; miR-137; presynaptic vesicles; sex differences; synapse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
CA1 Region, Hippocampal / pathology
CA1 Region, Hippocampal / ultrastructure
Conditioning, Operant
Dendrites / metabolism
Dendrites / ultrastructure
Female
Gene Deletion*
Gene Expression Regulation*
Genotype
Histones / metabolism
Lysine / metabolism
Magnetic Resonance Imaging
Male
Memory Disorders / genetics*
Memory Disorders / physiopathology*
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs / genetics*
MicroRNAs / metabolism
Neurons
Organ Specificity
RNA, Messenger / genetics
RNA, Messenger / metabolism
Sex Characteristics*
Spatial Learning*
Synapses / metabolism
Synapses / ultrastructure
X-linked Nuclear Protein / deficiency*
X-linked Nuclear Protein / metabolism

Substances

Histones
MIRN137 microRNA, mouse
MicroRNAs
RNA, Messenger
Atrx protein, mouse
X-linked Nuclear Protein
Lysine

Grants and funding

MOP142369/CIHR/Canada