Higashimori, H. | bioRxiv Science

bioRxiv2025

Mutations in ASH1L cause a neurodevelopmental disorder with sex differences in epilepsy and autism

To understand brain phenotypes associated with ASH1L, we performed both studies in mouse models and clinical phenotyping of human subjects. We found in mice that ASH1L mutations result in seizures, microcephaly, and also less complex dendritic morphology. When we analyzed human subjects based for epilepsy, intellectual disability, and ASD, we found sex differences in epilepsy and autism, with epilepsy predominantly in female and ASD in male subjects. To understand the cellular and molecular mechanisms of the sex-difference, we performed whole cell patch clamp electrophysiology in mice and found hyperexcitability in female compared with male hippocampal CA1 neurons. We report the identification of sex-specific transcriptomic signatures resulting from ASH1L haploinsufficiency. Differentially expressed genes in female mice showed distinct association with epileptic encephalopathy, postnatal microcephaly and autistic behaviors. Thus, the role of ASH1L in specific circuits may be sex-dependent leading to sexual dimorphic effects from disruption of this gene.

neuroscience↗

bioRxiv2020

Astroglial FMRP modulates synaptic signaling and behavior phenotypes in FXS mouse model

Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.

neuroscience↗