Voltage-Independent SK-Channel Dysfunction Causes Neuronal Hyperexcitability in the Hippocampus of Fmr1 Knock-Out Mice

• Type of Material: Article
• Authors: Pan-Yue Deng, Washington University; Dan Carlin, Washington University; Young Mi Oh, Washington University; Leila K. Myrick, Emory University; Stephen Warren, Emory University; Valeria Cavalli, Washington University; Vitaly A. Klyachko, Washington University
• Language: English
• Date: 2019-01-02
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2019 the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1593-18.2018
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 39
• Issue: 1
• Start Page: 28
• End Page: 43
• Grant/Funding Information: This work was supported by National Institute of Neurological Disorders and Stroke (NINDS) Grant R01 NS089449 to V.A.K. and by NINDS and National Institute of Child Health and Human Development Grant U54 NS091859 to S.T.W.
• Keywords: threshold; excitability; EXCITABILITY; FRAGILE-X-SYNDROME; Life Sciences & Biomedicine; SK channels; CA1 PYRAMIDAL NEURONS; MESSENGER-RNA; presynaptic function; PLASTICITY; action potential; FMRP; MENTAL-RETARDATION PROTEIN; K+ CHANNELS; POTASSIUM CHANNELS; CONDUCTANCE; MOUSE MODEL; Science & Technology; Neurosciences; Neurosciences & Neurology
• Research Categories: Biology, Neuroscience; Biology, Cell

Abstract

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K + )-channel dysfunction in hyperexcitability of CA3 pyramidal neurons in Fmr1 knock-out (KO) mice. We observed a reduction of voltage-independent small conductance calcium (Ca 2+ )-activated K + (SK) currents in both male and female mice, leading to decreased action potential (AP) threshold and reduced medium afterhyperpolarization. These SK-channel-dependent deficits led to markedly increased AP firing and abnormal input–output signal transmission of CA3 pyramidal neurons. The SK-current defect was mediated, at least in part, by loss of FMRP interaction with the SK channels (specifically the SK2 isoform), without changes in channel expression. Intracellular application of selective SK-channel openers or a genetic reintroduction of an N-terminal FMRP fragment lacking the ability to associate with polyribosomes normalized all observed excitability defects in CA3 pyramidal neurons of Fmr1 KO mice. These results suggest that dysfunction of voltage-independent SK channels is the primary cause of CA3 neuronal hyperexcitability in Fmr1 KO mice and support the critical translation-independent role for the fragile X mental retardation protein as a regulator of neural excitability. Our findings may thus provide a new avenue to ameliorate hippocampal excitability defects in FXS.