Mosaic expression of <i>Atrx</i> in the central nervous system causes memory deficits

Tamming, Renee J.; Siu, Jennifer R.; Jiang, Yan; Prado, Marco A. M.; Beier, Frank; Bérubé, Nathalie G.

doi:10.1242/dmm.027482

Cited by 15 publications

(20 citation statements)

References 44 publications

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“…Some of the molecular defects identified in these mice included decreased activation of CaMKII and the AMPA receptor in the hippocampus as well as decreased spine density in the medial prefrontal cortex, and altered DNA methylation and increased expression of Xlr3b in neurons 16 . Our group also reported similar behavioural impairments in female mice exhibiting mosaic expression of ATRX in the central nervous system 17 . However, the contribution of different cell types and sex difference to behavioural abnormalities have not yet been resolved.…”

Section: Introductionsupporting

confidence: 72%

“…These mechanisms could lead to protective gene regulation in the Atrx-cKO Fem , causing the sexually dimorphic defects in learning and memory. We previously reported impairment of spatial learning and memory in a female mouse model with mosaic expression of ATRX in all cells of the central nervous system 17 . This suggests the intriguing possibility that female-specific protective factors originate from cell types other than the excitatory neurons targeted in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…qRT-PCR was performed using the Y maze. Animals were placed in the center of a symmetrical three-armed Y maze as described 17,35 . Each mouse underwent one trial of 5 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…Novel object recognition. Mice were habituated in an open arena with no objects for 5 minutes on Day 1 and Day 2, as described 17 . On Day 3, mice were exposed to two identical objects for ten minutes (A; a red plastic ball attached on top of a yellow cube base).…”

Section: Methodsmentioning

confidence: 99%

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

Tamming

Dumeaux

Langlois

et al. 2019

Preprint

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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. AbstractMutations 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 ATRXdependent 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.

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Section: Introductionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

“…qRT-PCR was performed using the Y maze. Animals were placed in the center of a symmetrical three-armed Y maze as described 17,35 . Each mouse underwent one trial of 5 minutes.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Tamming

Dumeaux

Langlois

et al. 2019

Preprint

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“…Mice were placed in a 20 cm × 20 cm arena with 30 cm high walls. Locomotor activity was automatically recorded in 5-minute intervals over 2 hours (AccuScanInstrument)(30). For each mouse the number of vertical episodes was assessed.…”

Section: Methodsmentioning

confidence: 99%

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Martin-Kenny

Bérubé

2020

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24Background: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism 25 susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X 26 intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) 27 patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours 28 are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in 29 excitatory neurons of the forebrain and performed a battery of behavioural assays that assess 30 autistic-like behaviours. 31Methods: Male and female mice with a postnatal conditional knockout of Atrx were tested in a 32 battery of behavioural tests that assess autistic features. We utilized paradigms that measure social 33 behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were 34 calculated by two-way repeated measures ANOVA with Sidak's multiple comparison test or 35 unpaired Student's T-tests as indicated. 36Results: The behaviour tests revealed no significant differences between Atrx-cKO and control 37 mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, 38 these changes did not correlate with social deficits. We additionally observed sex-specific 39 differences in sociability, vertical episodes, and acoustic startle response when results were 40 analyzed by sex. 41 Conclusion: The postnatal knockout of Atrx in forebrain excitatory neurons does not lead to 42 autism-related behaviours in male or female mice.43 44 Keywords: autism spectrum disorder, ATRX, sex differences, social behaviours, repetitive 45 behaviours, startle response, genetically engineered mice, Cre/loxP system 46 Background 47 Autism spectrum disorder (ASD) is a behaviourally defined condition characterized by 48 deficits in social and communicative abilities, impaired sensory gating, as well as the presence of 49 stereotyped behaviours (1,2). Recent work has highlighted the important contribution of de novo 50 variants and inherited copy number variants in ASD, confirming a strong genetic component of 51 this disease (1-3). Numerous autism susceptibility genes have been identified and shown to share 52 commonalities in synaptic, transcriptional, and epigenetic mechanisms (4-6). Mouse models have 53typically been used to investigate the behavioural implications of genetic mutations associated 54 with ASD (7,8). However, these studies often omit the investigation of the sex-specific effects of 55 these genetic mutations, limiting the potential translational applications. In the general population, 56 ASD occurs at a 4:1 male:female ratio, highlighting the need to study the outcome of genetic 57 mutations in both male and female model systems (1,2). 58In this study, we describe the impact of targeted inactivation of Atrx in glutamatergic 59 neurons on behaviours related to autism in male and female mice. ATRX belongs to the SWI/SNF 60 family of chromatin remodeling factors (9,10). Mutations in ...

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The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

Mossink

Negwer

Schubert

et al. 2020

Cell. Mol. Life Sci.

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Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

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Mosaic expression of Atrx in the central nervous system causes memory deficits

Cited by 15 publications

References 44 publications

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

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

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

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