Abstracts

Rationale: Mutations in the histone methyltransferase Absent, small, or homeotic-like (ASH1L) are associated with autism with high penetrance. While some children with ASH1L mutations have mild autism/intellectual disability (ID) and few other symptoms, others have severe ID, no verbal communication, intractable seizures, and multiple congenital anomalies. Although no longitudinal clinical study of ASH1L has been completed, case reports suggest that approximately one- to two-thirds of affected children have seizures, which are often refractory to treatment.

Methods: To study how loss of ASH1L leads to ASD and seizures, I use mice with a gene-trap mutation in ASH1L, rendering the mice hypomorphic for ASH1L. To investigate the association between ASH1L and seizures, I performed 72-hour video EEG recording in ASH1L mutant and wild-type (WT) mice.

Results: While no WT mice had electrographic seizures, two-thirds (8 out of 12) of ASH1L mutant mice had electrographic seizures throughout the recording period. This approximates the prevalence of seizures in humans with ASH1L mutations, implying that the ASH1L mutant mouse model has good face validity. All seizures were focal hippocampal seizures, providing novel insight into seizure semiology after loss of ASH1L. Seizures were accompanied by severe interictal spiking and gliosis in the cortex and hippocampus, suggesting that seizures lead to sclerotic changes.
_x000D_ Despite the association of ASH1L mutations with autism and epilepsy, the electrophysiological properties of neurons in the ASH1L mutant brain have never been examined. To test whether loss of ASH1L has functional consequences on neuronal excitability, I performed whole-cell patch clamp electrophysiology on layer V pyramidal cells in somatosensory cortex. ASH1L mutant neurons had decreased firing rate and increased rheobase compared to WT neurons, while passive membrane properties were unchanged. This decreased intrinsic excitability could represent a primary defect in excitatory neurons, or a homeostatic adaptation to larger circuit perturbations. To test whether these changes in cellular excitability could affect larger brain rhythms, I compared baseline EEG power spectra between ASH1L mutant and WT mice. ASH1L mutant mice had increased cortical delta power as compared to WT.

Conclusions: Overall, I found cellular and circuit-level changes after loss of ASH1L, manifesting in seizures, altered brain rhythms, and decreased neuronal excitability. This study is the first to examine electrophysiological and seizure phenotypes in mice with ASH1L mutations. This work validates the ASH1L mutant mouse model for preclinical testing of therapeutic strategies to treat seizures in children with ASH1L mutations.

Funding: 1R01MH127081-01A1 - ASH1L-mediated transcription networks in autism spectrum disorders