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CGCM

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Cardiac Gene and Circuit Mechanisms (NS090340)


Specific Aims and Tasks

The primary mission of the SRA is to understand the basic biological mechanisms, genetic and physiological risk factors, predictive diagnostic biomarkers, and potential methods of preventing sudden unexpected death, the most common cause of premature mortality in human epilepsy. This project will test the principal hypothesis that mutation of single genes co-expressed in brain, heart, and brainstem central autonomic neurons increase SUDEP risk by promoting cardiorespiratory arrhythmias. We will identify and validate novel ictal bradycardia and SUDEP gene candidates in mouse models to expand the SUDEP risk genome, and use modifier genes that suppress this risk in forebrain and brainstem autonomic circuits to genetically dissect critical SUDEP pathways. We will examine molecular excitability mechanisms perturbed by these genes in brain and heart, and the role of seizures and hypoxia in pathological network depolarization. We will also explore translational pharmacologic and genetic rescue strategies in these models. These findings will contribute to future genetic risk profiling for SUDEP in clinical exomes and point to new gene-directed approaches to reduce SUDEP in patients at high risk.

Principal Investigators



Publication Links

  • Aibi I, Wehrens XH, Noebels JL. Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death. Proc Natl Acad Sci U S A. 2016 Aug 16;113(33). PMID 27482086.
  • Buchanan, G.F. & G.B. Richerson. Epilepsy: A dietary supplement for SUDEP prevention? Nature Rev Neurol 12(9):495-6, 2016. PMID 27514288.
  • Devinsky, O., D.C. Hesdorffer, D. Thurman, S. Lhatoo, G.B. Richerson. Sudden Unexpected Death in Epilepsy: Epidemiology, Mechanisms & Prevention. Lancet Neurology, 15(10):1075-88, 2016. PMID 27571159.
  • Hernandez CC, Klassen TL, Jackson LG, Gurba K, Hu N, Noebels JL, Macdonald RL. Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population. PLoS One. 2016 Sep 13;11(9). PMID 27622563.
  • Noebels J. Hippocampal abnormalities and sudden childhood death. Forensic Sci Med Pathol. 2016 Jun;12(2):198-9. PMID 27094436.
  • Richerson, G.B., D. Boison, C. Faingold & P. Ryvlin. SUDEP: From unwitnessed fatality to witnessed rescue: pharmacological intervention. Epilepsia, 57(Suppl 1):35-45, 2016. PMID 26749015.
  • Aiba I, Noebels JL. Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med. 2015 Apr 8;7(282):282ra46. PMID 25855492.
  • Bernard C. Spreading depression: epilepsy’s wave of death. Sci Transl Med. 2015 Apr 8;7(282):282fs14. PMID 25855491.
  • Buchanan, G.F., H. Smith, A. MacAskill & G.B. Richerson. 5-HT2A receptor activation is necessary for CO2-induced arousal. J Neurophysiol, 114(1):233-43, 2015. PMID 25925320.
  • Cerpa, V.J., M.L. Aylwin, S. Beltrán-Castillo, E.U. Bravo, I.R. Llona, G.B. Richerson & J.L. Eugenín. Alteration of neonatal raphe neurons by prenatal-perinatal nicotine: Meaning for Sudden Infant Death Syndrome. Am J Respir Cell Mol Biol, 53(4):489-99, 2015. PMID 25695895.
  • Dlouhy, B.J., B.K. Gehlbach, C.J. Kreple, H. Kawasaki, H. Oya, C. Buzza, M.A. Granner, M.J. Welsh, M.A. Howard III, J.A. Wemmie and G.B. Richerson. Breathing inhibited when seizures spread to the amygdala and upon amygdala stimulation. J Neurosci, 35(28):10281-9, 2015. PMID 26180203.
  • Dlouhy, B.J., B.K. Gehlbach & G.B. Richerson. Sudden unexpected death in epilepsy (SUDEP): basic mechanisms and clinical implications for prevention. J Neurol Neurosurg Psych, 87(4):402-13, 2015. PMID 26979537.
  • Corcoran, A.E., G.B. Richerson & M.B. Harris. Functional link between the hypocretin and serotonin systems in the neural control of breathing and central chemosensitivity. J Neurophysiol, 114(1):381-9, 2015. PMID 25878157.
  • Glasscock E, Voigt N, McCauley MD, Sun Q, Li N, Chiang DY, Zhou XB, Molina CE, Thomas D, Schmidt C, Skapura DG, Noebels JL, Dobrev D, Wehrens XH. Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation. Basic Res Cardiol. 2015 Sep;110(5):505. PMID 26162324.
  • Lhatoo, S., J. Noebels, V. Whittemore, and The NINDS Center for SUDEP Research. Sudden Unexpected Death in Epilepsy (SUDEP): Identifying Risk and Preventing Mortality. Epilepsia 56(11):1700-6, 2015. PMID 26494436.
  • Massey, C.A., K.E. Iceman, S.L. Johansen, Y. Wu, M.B. Harris & George B. Richerson. Isoflurane abolishes spontaneous firing of serotonin neurons and masks their pH/CO2 chemosensitivity. J Neurophysiol, 113(7):2879-88, 2015. PMID 25695656.
  • McGlashon, J.B., A. Kozlowski, M. Gorecki, C. Thirnbeck, K. Markan, M.E. Kotas, M.J. Potthoff, G.B. Richerson & M.P. Gillum. Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell Metabolism, 21(5):692-705, 2015. PMID 25955206.
  • Murray, N.M., G.F. Buchanan & G.B. Richerson. Sleep disruption caused by serotonin depletion is due to hypothermia. Sleep, 38(12):1985-93, 2015. PMID 26194567.
  • Noebels J. Pathway-driven discovery of epilepsy genes. Nat Neurosci. 2015 Mar;18(3):344-50. PMID 25710836.
  • Noebels JL. Single-Gene Determinants of Epilepsy Comorbidity. Cold Spring Harb Perspect Med. 2015 Nov 2;5(11). PMID 26525453.
  • Klassen TL, Bomben VC, Patel A, et al. High-resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile. PMID 24372310.
  • Qi Y, Wang J, Bomben VC, Li DP, Chen SR, Sun H, Xi Y, Reed JG, Cheng J, Pan HL, Noebels JL, Yeh ET. Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death. Neuron. 2014 Sep 3;83(5):1159-71. doi: 10.1016/j.neuron.2014.07.042. PMID 25189211.
  • Cole AJ, Eskandar E, Mela T, Noebels JL, Gonzalez RG, McGuone D. N Engl J Med. 2013 368:2304Case records of the Massachusetts General Hospital. Case 18-2013: a 32-year-old woman with recurrent episodes of altered consciousness. PMID 23758236.
  • Holth JK, Bomben VC, Reed JG, Inoue T, Youngkin L, Youngkin SG, Pautler RG, Botas J, Noebels, JL. Tau loss attenuates neuronal network hyperexcitability in mouse and drosophila genetic models of epilepsy. PMID 23345237.
  • Glasscock E, Qian J, Kole MJ, Noebels JL. Transcompartmental reversal of single fiber hyperexcitability in juxtaparanodal Kv1.1 –deficient vagus nerve axons by activation of nodal KCNQ channels. PMID 22641786.
  • Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. PMID 21703448.
  • Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia of Heart and Brain: KCNQ1 mutations link epilepsy and sudden death. Science Translational Medicine 2009, 1:98-106. PMID 20368164.
  • Glasscock, E, Yoo J, Chen TT, Klassen TL, Noebels JL Kv1.1 Potassium Channel Deficiency Reveals Brain-Driven Cardiac Dysfunction as a Candidate Mechanism for Sudden Unexplained Death in Epilepsy. PMID 20392939.
  • Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia of Heart and Brain: KCNQ1 mutations link epilepsy and sudden death. Science Translational Medicine 2009, 1:98-106. PMID 20368164.
  • Glasscock E, Qian J, Yoo JW, Noebels JL. Masking Epilepsy by Combining Two Epilepsy Genes. PMID 17982453.
  • Lopez-Santiago LF, Meadows LS, Ernst SJ, Chen C, Malhotra JD, McEwen DP, Speelman A, Noebels JL, Maier SK, Lopatin AN, Isom LL. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. PMID 17884088.
  • Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Ly NB, Yoo JW, Ho1 KO, Yu1 GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. PMID 17785178 .
  • Brenner R, Chen QH, Vilaythong A, Toney GM, Noebels JL, Aldrich RW. Deletion of BK Channel β4 Subunit Increases Dentate Granule Cell Excitability and Causes Non-Convulsive Temporal Lobe Seizures. http://www.nature.com/neuro/journal/v8/n12/abs/nn1573.html.
  • Chen C, Westenbroek RE, Xu X, Edwards CA, Sorenson DR, Chen Y, McEwen DP, O'Malley H, Bharucha V, Meadows LS, Knudsen GA, Vilaythong A, Noebels JL, Saunders TL, Scheuer T, Shrager P, Catterall WA, Isom LL. Mice Lacking Sodium Channel 1 Subunits Display Defects in Neuronal Excitability, Sodium Channel Expression, and Nodal Architecture. PMID 15102918.
  • Hartman HA, Colom LV, Sutherland ML, Noebels JL. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. PMID 10404176.
  • Burgess D.L., Jones J., Meisler M., Noebels J.L. Mutation of the Ca2+ channel subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. PMID 9039265.