In the vertebrate nervous system, a large 480 kDa splice variant of ankyrin-G is responsible for the formation of the axon initial segment and nodes of Ranvier, critical sites of clustered voltage-gated sodium channels that are necessary for normal neuronal signaling . A truncating mutation in the giant exon of ankyrin-G causes autism and marked cognitive dysfunction (IQ less than 50) . Importantly, ankyrin-G also has been linked to bipolar disorder in genome-wide association studies . The 480 kDa splice variant of ankyrin-G is necessary for the formation of inhibitory connections in the cortex and hippocampus . Interneurons that release γ-aminobutyric acid (GABA) are a major source of inhibitory signaling in vertebrate nervous systems, and defects in these circuits are strongly associated with neuropsychiatric disorders. Our laboratory examines how human variants affect the formation of inhibitory circuits in mouse models and in samples derived from human patients with the hopes of identifying therapeutic pathways for the restoration of these critical neuronal connections.
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- Tseng, W.C., P.M. Jenkins, M. Tanaka, R. Mooney, and V. Bennett, Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABAA receptors. Proc Natl Acad Sci U S A, 2015. 112(4): p. 1214-9.
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- Jenkins PM*, He M*, Bennett V. Dynamic spectrin/ankyrin-G microdomains promote lateral membrane assembly by opposing endocytosis. Sci. Adv. 2015; 1(8):e1500301