Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K⁺channels

Abstract

Neuronal ankyrins cluster and link membrane proteins to the actin and spectrin-based cytoskeleton. Among the three vertebrate ankyrins, little is known about neuronal Ankyrin-R (AnkR). We report AnkR is highly enriched in Pv+ fast-spiking interneurons in mouse and human. We identify AnkR-associated protein complexes including cytoskeletal proteins, cell adhesion molecules (CAMs), and perineuronal nets (PNNs). We show that loss of AnkR from forebrain interneurons reduces and disrupts PNNs, decreases anxiety-like behaviors, and changes the intrinsic excitability and firing properties of Pv+ fast-spiking interneurons. These changes are accompanied by a dramatic reduction in Kv3.1b K+ channels. We identify a novel AnkR-binding motif in Kv3.1b, and show that AnkR is both necessary and sufficient for Kv3.1b membrane localization in interneurons and at nodes of Ranvier. Thus, AnkR regulates Pv+ fast-spiking interneuron function by organizing ion channels, CAMs, and PNNs, and linking these to the underlying β1 spectrin-based cytoskeleton.

Ankyrin-dependent Na+ channel clustering prevents neuromuscular synapse fatigue

“…Ank1 f/f , Ank2 f/f , or Ank3 f/f mice were all described previously. 7,33,34 Animals were housed with a 12/12 h light/dark cycle and free access to food and water. Both male and female mice were used in our experiments.…”

Architecture of the human erythrocyte ankyrin-1 complex

“…Ankyrin-1 was first identified in erythrocytes 3 , where it mediates the attachment of the band 3 anion transport protein (AE1; SLC4A1) to spectrin 4 . It is also found in other tissues, including skeletal muscle and brain, where it has recently been shown to mediate clustering of Kv3.1b K+ channels in specific neuronal subtypes 5 . Ankyrin 2 and 3 play pivotal roles as dynamic adaptor platforms in cardiomyocytes and striated muscle cells 6 , and in neurons of the central 7 and peripheral 8 nervous systems, respectively.…”