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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Stewart, Randall R
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Vanderbilt University Medical Center
Schools of Medicine
United States
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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
Johnston, Ann J; Kang, Jing-Qiong; Shen, Wangzhen et al. (2014) A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes. Neurobiol Dis 64:131-41
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
Delahanty, R J; Kang, J Q; Brune, C W et al. (2011) Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Mol Psychiatry 16:86-96
Hernandez, Ciria C; Gurba, Katharine N; Hu, Ningning et al. (2011) The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6ýý22 and 6ýý2 GABA(A) receptor channel gating and expression. J Physiol 589:5857-78
Ding, Li; Feng, Hua-Jun; Macdonald, Robert L et al. (2010) GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem 285:26390-405
Tang, Xin; Hernandez, Ciria C; Macdonald, Robert L (2010) Modulation of spontaneous and GABA-evoked tonic alpha4beta3delta and alpha4beta3gamma2L GABAA receptor currents by protein kinase A. J Neurophysiol 103:1007-19
Belelli, Delia; Harrison, Neil L; Maguire, Jamie et al. (2009) Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci 29:12757-63
Kang, Jing-Qiong; Shen, Wangzhen; Macdonald, Robert L (2009) The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression. J Neurosci 29:2845-56
Feng, Hua-Jun; Botzolakis, Emmanuel J; Macdonald, Robert L (2009) Context-dependent modulation of alphabetagamma and alphabetadelta GABA A receptors by penicillin: implications for phasic and tonic inhibition. Neuropharmacology 56:161-73

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