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Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

Renee J. Tamming, Vanessa Dumeaux, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Yan Jiang, Jason P. Lerch, Nathalie G. Bérubé
doi: https://doi.org/10.1101/606442
Renee J. Tamming
Children’s Health Research Institute, London, CanadaLawson Health Research Institute, London, CanadaDepartment of Biochemistry, Western University, London, Canada
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Vanessa Dumeaux
Department of Paediatrics, Western University, London, CanadaPERFORM Centre, Concordia University, The Hospital for Sick Children, Toronto, Canada
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Luana Langlois
Children’s Health Research Institute, London, CanadaLawson Health Research Institute, London, CanadaDepartment of Anatomy & Cell Biology, Western University, London, Canada
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Jacob Ellegood
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Canada
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Lily R. Qiu
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Canada
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Yan Jiang
Children’s Health Research Institute, London, CanadaLawson Health Research Institute, London, Canada
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Jason P. Lerch
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, CanadaDepartment of Medical Biophysics, The University of Toronto, Toronto, CanadaWellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK
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Nathalie G. Bérubé
Children’s Health Research Institute, London, CanadaLawson Health Research Institute, London, CanadaDepartment of Paediatrics, Western University, London, CanadaDepartment of Anatomy & Cell Biology, Western University, London, CanadaDepartment of Oncology, Western University, London, Canada
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  • For correspondence: nberube@uwo.ca
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Abstract

Mutations in the ATRX chromatin remodeler are associated with syndromic and non-syndromic intellectual disability. Emerging evidence points to key roles for ATRX in preserving neuroprogenitor cell genomic stability, whereas ATRX function in differentiated neurons and memory processes are still unresolved. Here, we show that Atrx deletion in mouse forebrain glutamatergic neurons causes distinct hippocampal structural defects identified by magnetic resonance imaging. Ultrastructural analysis revealed fewer presynaptic vesicles and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. These synaptic defects are associated with impaired long-term contextual memory in male, but not female mice. Mechanistically, we identify ATRX-dependent and sex-specific alterations in synaptic gene expression linked to Mir137 levels, a known regulator of presynaptic processes and spatial memory. We conclude that ablation of Atrx in excitatory forebrain neurons leads to sexually dimorphic outcomes on miR-137 and on spatial memory, identifying a promising therapeutic target for neurological disorders caused by ATRX dysfunction.

Summary statement Ablation of the ATRX chromatin remodeler specifically in forebrain excitatory neurons of mice causes male-specific deficits in long-term spatial memory associated with miR-137 overexpression, transcriptional changes and structural alterations corresponding to pre- and post-synaptic abnormalities.

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Posted April 13, 2019.
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Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits
Renee J. Tamming, Vanessa Dumeaux, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Yan Jiang, Jason P. Lerch, Nathalie G. Bérubé
bioRxiv 606442; doi: https://doi.org/10.1101/606442
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Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits
Renee J. Tamming, Vanessa Dumeaux, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Yan Jiang, Jason P. Lerch, Nathalie G. Bérubé
bioRxiv 606442; doi: https://doi.org/10.1101/606442

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