Mechanisms of Alcohol Withdrawal Seizures: Role of L-type Ca2+ Channels

Summary

Principal Investigator: PROSPER N'GOUEMO
Abstract: DESCRIPTION (provided by applicant): Alcohol withdrawal seizures (AWS) are one of the most common medical emergencies, but their underlying mechanisms are poorly understood. The inferior colliculus (IC) is thought to play an important role in initiating acoustically-evoked AWS. In a rat model, epileptiform bursts from IC neurons are critical in initiating acoustically-evoked AWS, and dihydropyridines (L-type Ca2+ channels blockers) suppressed these seizures. The extent to which L-type Ca2+ channels (LTCCs) contribute to generating epileptiform bursts in IC neurons following alcohol withdrawal is unknown. Which of the two LTCC classes (CaV1.2 and CaV1.3) present in IC neurons contribute to AWS is also unknown. Our overall goal is to understand how controlling LTCCs and related Ca2+ signaling can be use to prevent and treat AWS. The objective of this application is to investigate AWS etiology in rats and mice by determining the role of LTCCs in the mechanisms underlying IC neuronal hyperexcitability in response to alcohol withdrawal. Our central hypothesis is that CaV1.3 LTCC activity is required for IC neurons to generate epileptiform bursts that initiate AWS. This hypothesis is based on substantial preliminary data from our rat AWS model, with further support from published reports that: i) blockade of LTCCs suppresses acoustically-evoked AWS, ii) the current density of LTCCs increases markedly in IC neurons following alcohol withdrawal associated with enhanced seizure susceptibility, and iii) LTCCs of the other class, CaV1.2, are not upregulated in IC neurons following alcohol withdrawal. The rationale for the proposed research is that understanding the role of LTCCs in AWS initiation has the potential to improve our ability to prevent and control these seizures. Our central hypothesis will be tested by pursuing three specifics aims: 1) Determine to what extent LTCCs contribute to generating epileptiform bursts and Ca2+ spikes in IC neurons following alcohol withdrawal;2) Determine to what extent phosphorylation, cell surface protein expression, and mRNA expression of CaV1.3 LTCCs are associated with the enhanced current density in IC neurons following alcohol withdrawal;and 3) Determine if acoustically-evoked AWS can be generated in CaV1.3a1 knockout mice and rats in which CaV1.3a1 subunits are knocked down by short-interfering RNA microinjection into IC neurons. Our approach is innovative because it uses molecular genetics combined with electrophysiology and pharmacology to determine the role of CaV1.3 LTCCs in IC neuronal hyperexcitability and resulting AWS. Our proposed research is significant because the experiments will identify an LTCC- dependent mechanism essential to AWS initiation, fundamentally advancing the field of alcohol abuse and identifying a new molecular target for novel therapeutic approaches to AWS prevention and treatment. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
Funding Period: 2011-08-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Targeting BK (big potassium) channels in epilepsy
    PROSPER N'GOUEMO
    Georgetown University Medical Center, Interdisciplinary Program in Neuroscience and Department of Pediatrics, Washington, DC 20057, USA
    Expert Opin Ther Targets 15:1283-95. 2011
  2. pmc Alcohol withdrawal is associated with a downregulation of large-conductance Ca²⁺-activated K⁺ channels in rat inferior colliculus neurons
    PROSPER N'GOUEMO
    Department of Pediatrics, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC, 20057, USA
    Psychopharmacology (Berl) 231:2009-18. 2014

Detail Information

Publications2

  1. pmc Targeting BK (big potassium) channels in epilepsy
    PROSPER N'GOUEMO
    Georgetown University Medical Center, Interdisciplinary Program in Neuroscience and Department of Pediatrics, Washington, DC 20057, USA
    Expert Opin Ther Targets 15:1283-95. 2011
    ..This unique coupling of Ca2+ signaling to membrane depolarization is important in controlling neuronal hyperexcitability, as outward K+ current through BKCa channels hyperpolarizes neurons...
  2. pmc Alcohol withdrawal is associated with a downregulation of large-conductance Ca²⁺-activated K⁺ channels in rat inferior colliculus neurons
    PROSPER N'GOUEMO
    Department of Pediatrics, Georgetown University Medical Center, 3900 Reservoir Rd, NW, Washington, DC, 20057, USA
    Psychopharmacology (Berl) 231:2009-18. 2014
    ..Large conductance calcium-activated potassium (BK(Ca) or K(Ca)1.1) channels are well-known molecular targets for the action of alcohol and therefore may play an important role in the pathogenesis of alcohol withdrawal syndrome...

Research Grants30

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