Alterations in intrinsic membrane properties and the axon initial segment in a mouse model of Angelman syndrome

The axon initial segment (AIS) is the site of action potential initiation in neurons. Recent studies have demonstrated activity-dependent regulation of the AIS, including homeostatic changes in AIS length, membrane excitability, and the localization of voltage-gated Na ⁺ channels. The neurodevelopmental disorder Angelman syndrome (AS) is usually caused by the deletion of small portions of the maternal copy of chromosome 15, which includes the UBE3A gene. A mouse model of AS has been generated and these mice exhibit multiple neurological abnormalities similar to those observed in humans.Weexamined intrinsic properties of pyramidal neurons in hippocampal area CA1 from AS model mice and observed alterations in resting membrane potential, threshold potential, and action potential amplitude. The altered intrinsic properties in the AS mice were correlated with significant increases in the expression of the α1 subunit of Na/K-ATPase (α 1-NaKA), the Na ⁺ channel NaV1.6, and the AIS anchoring protein ankyrin-G, as well as an increase in length of the AIS. These findings are the first evidence for pathology of intrinsic membrane properties and AIS-specific changes in AS, a neurodevelopmental disorder associated with autism.