Investigating the Role of ATRX in Glutamatergic Hippocampal Neurons

Mutations in ATRX, a Snf2-type chromatin remodeler, frequently lead to intellectual disability. However, the function of ATRX within the brain in cognition and synaptic transmission are incompletely understood. The aim of this study was to investigate the role of ATRX in the adult mouse brain. While complete loss of ATRX in the embryonic mouse brain results in perinatal lethality, mosaic expression of ATRX stunted growth and perturbed circulating IGF-1 levels. Mosaic expression of ATRX also impaired adult cognition, specifically recognition memory and spatial learning and memory. However, there were confounding factors that led me to a new model in which I deleted the gene in postnatal mouse glutamatergic neurons. Magnetic resonance imaging of these mice revealed increased hippocampal CA1 and CA3 layers, and behaviour analysis indicated deficiencies in hippocampal-dependent learning and memory in the contextual fear task, Morris water maze, and paired-associate learning task. These behavioural abnormalities were not present in the female counterparts. Transmission electron microscopy of male hippocampal CA1 synapses revealed decreased number of total and docked vesicles and increased cleft width and post-synaptic density size. Hippocampal RNA-sequencing followed by sex-interaction analysis of male and female knockout transcripts highlighted potential impairments in the synaptic vesicle cycle. miR-137, a known regulator of presynaptic vesicle cycle and plasticity, was upregulated in the male knockout hippocampi but downregulated in the female knockouts. These results demonstrate sexually-dimorphic regulation of miR-137 and learning and memory by ATRX in forebrain glutamatergic neurons, indicating potential miRNA-targeting therapies for cognitive disorders by ATRX mutations

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

The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX protein expression in the central nervous system attributable to the location of the gene on the X chromosome. Although the hemizygous male mice die soon after birth, heterozygous females survive to adulthood. Body growth is stunted in these animals, and they have low circulating concentrations of insulin growth factor 1. In addition, they are impaired in spatial, contextual fear and novel object recognition memory. Our findings demonstrate that mosaic loss of ATRX expression in the central nervous system leads to endocrine defects and decreased body size and has a negative impact on learning and memory

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

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

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

The rapid modulation of chromatin organization is thought to play a crucial role in cognitive processes such as memory consolidation. This is supported in part by the dysregulation of many chromatin-remodelling proteins in neurodevelopmental and psychiatric disorders. A key example is ATRX, an X-linked gene commonly mutated in individuals with syndromic and nonsyndromic intellectual disability. The consequences of Atrx inactivation for learning and memory have been difficult to evaluate because of the early lethality of hemizygous-null animals. In this study, we evaluated the outcome of brain-specific Atrx deletion in heterozygous female mice. These mice exhibit a mosaic pattern of ATRX protein expression in the central nervous system attributable to the location of the gene on the X chromosome. Although the hemizygous male mice die soon after birth, heterozygous females survive to adulthood. Body growth is stunted in these animals, and they have low circulating concentrations of insulin growth factor 1. In addition, they are impaired in spatial, contextual fear and novel object recognition memory. Our findings demonstrate that mosaic loss of ATRX expression in the central nervous system leads to endocrine defects and decreased body size and has a negative impact on learning and memory