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

Tamming, Renee J.; Dumeaux, Vanessa; Jiang, Yan; Shafiq, Sarfraz; Langlois, Luana; Ellegood, Jacob; Qiu, Lily R.; Lerch, Jason P.; Bérubé, Nathalie G.

doi:10.1016/j.celrep.2020.107838

Cited by 17 publications

(29 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using transmission electron microscopy, we previously reported that ATRX‐cKO mice have a significant reduction in the number of presynaptic vesicles, a wider synaptic cleft, and a larger postsynaptic density in the CA1 stratum radiatum compared to controls (Tamming et al, ). While a wider synaptic cleft is expected to result in slower onset or duration of excitatory synaptic responses, our field potential analyses were unable to detect any such changes between groups (results not shown).…”

Section: Discussionmentioning

confidence: 99%

“…However, they displayed deficits when tested a week later, suggesting long‐term spatial memory impairment in these mice. They also displayed impaired contextual fear memory, compared to controls, 24 hr after conditioning, and exhibited a drastic deficit when tested in the paired‐associate learning touchscreen task, which relies on the hippocampus (Tamming et al, ). The decrease of hippocampal apical dendritic CA1 LTP that we identified in the present study may account for the hippocampus‐dependent learning and memory impairment in ATRX‐cKO mice.…”

Section: Discussionmentioning

confidence: 99%

“…These deficits in synaptic transmission and plasticity may contribute to intellectual disability in ATR‐X syndrome patients and to the long‐term spatial memory deficit observed in ATRX‐cKO male mice. Because ATRX‐cKO female mice do not display the same spatial learning and memory deficit as males (Tamming et al, ), it will be important in future studies to investigate whether hippocampal synaptic transmission and plasticity is dimorphic between male and female mice upon loss of neuronal ATRX.…”

Section: Discussionmentioning

confidence: 99%

“…In order to bypass the severe outcomes of Atrx inactivation in proliferating cells, we recently generated another mouse model featuring conditional ablation of Atrx in postnatal forebrain pyramidal neurons (ATRX‐cKO mice). Male, but not female, ATRX‐cKO mice were deficient in hippocampus‐dependent learning and memory (Tamming et al, ). In addition, male ATRX‐cKO mice had distinct synaptic ultrastructural defects and RNA sequencing revealed an altered transcriptional profile in the hippocampus linked to increased levels of miR‐137 (Tamming et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Male, but not female, ATRX‐cKO mice were deficient in hippocampus‐dependent learning and memory (Tamming et al, ). In addition, male ATRX‐cKO mice had distinct synaptic ultrastructural defects and RNA sequencing revealed an altered transcriptional profile in the hippocampus linked to increased levels of miR‐137 (Tamming et al, ).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

et al. 2019

Self Cite

View full text Add to dashboard Cite

α-Thalassemia X-linked intellectual disability (ATR-X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2-type chromatinremodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX-cKO) causes deficits in long-term hippocampus-dependent spatial memory. Thus, we hypothesized that ATRX-cKO mice will display impaired hippocampal synaptic transmission and plasticity.In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane-anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including pairedpulse facilitation (PPF) at 50-ms interpulse interval, and by their long-term potentiation (LTP) induced by theta-frequency burst stimulation. Baseline single-pulse excitatory response at each synapse did not differ between ATRX-cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX-cKO mice. While basal dendritic LTP of the first-pulse excitatory response was not affected in ATRX-cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long-term spatial memory deficits in ATRX-cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR-X syndrome patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

Menin Deficiency Induces Autism‐Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1‐Related Encephalopathy

Zhuang,

Leng,

et al. 2024

Advanced Science

View full text Add to dashboard Cite

FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism‐like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X‐Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over‐expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1‐related encephalopathy.

show abstract

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

Mossink

Negwer

Schubert

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 17 publications

References 99 publications

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

Menin Deficiency Induces Autism‐Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1‐Related Encephalopathy

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

Contact Info

Product

Resources

About