Alterations in Intrinsic Membrane Properties and the Axon Initial Segment in a Mouse Model of Angelman Syndrome

Abstract

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. We examined 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 (α1-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.

Polarized localization of voltage-gated Na + channels is regulated by concerted FGF13 and FGF14 action

“…An initial clue that these VGSC regulators may have distinct, nonredundant roles came from their strikingly dissimilar subcellular distributions within the same neuron. As expected by its localization to the axons of cerebellar granule neurons (23) and previous work in hippocampal neurons (31,32), FGF14 was concentrated in the axons of cultured hippocampal neurons (Fig. 1C, Left).…”

“…Having thus validated the specificity of our Ab, we observed FGF13 localization in the hippocampus in brain slices, wherein the FGF13 signal is prominent in pyramidal neurons (Fig. 1B, Left), a cell population in which FGF14 is also highly expressed (31,32). As in cultured hippocampal neurons, FGF13 localized to axons (Fig.…”

“…To gain insight into possible regulatory roles for FGF13 and FGF14, we first examined their neuronal localizations. Although the localization of FGF14 to the axons of neurons has been well studied (23,31,32), the localization of FGF13 in the CNS has not been as extensively detailed. We have previously used a custom-made FGF13 Ab and FGF13 shRNA to examine FGF13 function in cardiomyocytes (33,34).…”

Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

“…Recent studies have identified several neuronal proteins that are mis-regulated in AS neurons, including CAMKII, RhoA guanine nucleotide exchange factor 5 (EPHEXIN5), activity-regulated cytoskeleton-associated protein (ARC), GAT1, α1-NAKA, NAV1.6, and ANKYRIN-G (8)(9)(10)(11)(12). Some of these proteins are thought to be direct substrates of UBE3A.…”

“…AS mice have significant neural circuit defects, suggesting that in the absence of Ube3a there is a disruption of excitatory/ inhibitory balance in the brain (6,10,12,13,(17)(18)(19). In addition, AS mice display defects in learning and memory, motor coordination, locomotor activity (14,17,20,21), and an increased number of seizures when exposed to an audiogenic challenge (6,11).…”