GABAA receptors (GABARs) are the primary mediators of fast inhibitory synaptic transmission and tonic extrasynaptic inhibition. Synaptic GABARs are composed of 1, 2, and 32 subunits while extrasynaptic GABARs are generally composed of 1, 2, and 4 subunits. Mutations and variants in GABAR 32 and 4 subunit genes have recently been associated with idiopathic generalized epilepsies (IGEs). Our long-term goals are to understand how these mutations and variants disrupt the normal assembly, surface trafficking, synaptic and extrasynaptic targeting, and surface stability of GABARs;to characterize the effects of these mutations on GABAR functional properties;and ultimately, to provide a mechanistic foundation for development of novel therapeutic strategies. Hypotheses to be tested are: 1) Assembly, trafficking, and functional properties of synaptic 1(1,2,3,4)2232 GABARs have strict subunit and cellular requirements;2) Assembly, trafficking, and functional properties of extrasynaptic 1(1,4)224 and 152232 GABARs have strict subunit and cellular requirements;and 3) 32 subunit mutations and 4 subunit variants promote neuronal hyperexcitability by altering assembly, surface trafficking, and/or function of synaptic 1(1,2,3,4)2232 and extrasynaptic 1(1,4)224 and 152232 GABARs.
Specific aims are: 1) To determine how synaptic 1(1,2,3,4)2232 GABARs are assembled and trafficked to the cell surface and to characterize their functional properties;2) Specific Aim 2: To determine how extrasynaptic 1(1,4)224 and 152232 GABARs are assembled and trafficked to the cell surface and to characterize their functional properties;and 3) : To determine how 32 subunit mutations and 4 subunit variants associated with IGEs disrupt subunit assembly, trafficking, and/or functional properties of synaptic and extrasynaptic GABARs.

Public Health Relevance

Epilepsy affects more than 0.5 % of the world's population and genetic factors play an important role in many generalized and in some partial epilepsies. At the present time there is treatment for genetic epilepsies with antiepileptic drugs but there is no cure. This proposal seeks to determine the basis for the genetic epilepsies associated with mutations in the inhibitory neurotransmitter GABAA receptor subunit genes that will provide a mechanistic foundation for development of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033300-16
Application #
7989388
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
1995-05-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2011
Total Cost
$329,066
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hernandez, Ciria C; Kong, Weijing; Hu, Ningning et al. (2017) Altered Channel Conductance States and Gating of GABAA Receptors by a Pore Mutation Linked to Dravet Syndrome. eNeuro 4:
Ishii, Atsushi; Kang, Jing-Qiong; Schornak, Cara C et al. (2017) A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet 54:202-211
Shen, Dingding; Hernandez, Ciria C; Shen, Wangzhen et al. (2017) De novo GABRG2 mutations associated with epileptic encephalopathies. Brain 140:49-67
Botzolakis, Emmanuel J; Gurba, Katharine N; Lagrange, Andre H et al. (2016) Comparison of ?-Aminobutyric Acid, Type A (GABAA), Receptor ??? and ??? Expression Using Flow Cytometry and Electrophysiology: EVIDENCE FOR ALTERNATIVE SUBUNIT STOICHIOMETRIES AND ARRANGEMENTS. J Biol Chem 291:20440-61
Hernandez, Ciria C; Klassen, Tara L; Jackson, Laurel G et al. (2016) Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population. PLoS One 11:e0162883
Kang, Jing-Qiong; Macdonald, Robert L (2016) Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome. JAMA Neurol 73:1009-16
Janve, Vaishali S; Hernandez, Ciria C; Verdier, Kelienne M et al. (2016) Epileptic encephalopathy de novo GABRB mutations impair GABAA receptor function. Ann Neurol :
Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen et al. (2015) The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. Nat Neurosci 18:988-96
Huang, Xuan; Hernandez, Ciria C; Hu, Ningning et al. (2014) Three epilepsy-associated GABRG2 missense mutations at the ?+/?- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. Neurobiol Dis 68:167-79
Lo, Wen-Yi; Lagrange, Andre H; Hernandez, Ciria C et al. (2014) Co-expression of ?2 subunits hinders processing of N-linked glycans attached to the N104 glycosylation sites of GABAA receptor ?2 subunits. Neurochem Res 39:1088-103

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