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Title page for ETD etd-04022019-141443

Type of Document Dissertation
Author Satpute Janve, Vaishali
Author's Email Address vaishali.c.satpute@vanderbilt.edu
URN etd-04022019-141443
Title Epileptic encephalopathy associated human GABRB mutations disrupt GABAA receptor function and results in Lennox-Gastaut syndrome in Gabrb3+/D120N knock-in mice.
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Dr. Bruce D. Carter Committee Chair
Dr. Andre H. Lagrange Committee Member
Dr. Jennifer A. Kearney Committee Member
Dr. Jerod S. Denton Committee Member
Dr. Robert L. Macdonald Committee Member
  • mouse model
  • pediatric
  • Epilepsy
  • GABAA receptor mutations
  • Lennox-Gastaut syndrome
Date of Defense 2019-02-11
Availability restrictone
Epileptic encephalopathies (EEs) are catastrophic childhood epilepsies with intractable seizures, developmental delays, and cognitive impairment. I determined the functional impact of five de novo GABAA receptor β subunit gene (GABRB) mutations identified in triads with a proband with one of two EEs⎯Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). In HEK293T cells, the major effects of the LGS-associated GABRB3(D120N, E180G, Y302C) mutations were reduced GABA-evoked currents due to reduced channel open probability and burst duration. While IS-associated GABRB3(N110D) and GABRB1(F246S) mutations altered current rise time and deactivation due to reduced channel open probability and burst duration for the GABRB3(N110D) mutation, and reduced channel conductance and opening frequency for the GABRB1(F246S) mutation. These alterations in GABAA receptor channel function should reduce neuronal inhibition, leading to seizures. Thus, these data provide strong evidence for a contribution of GABRB mutations to LGS and IS pathology. To understand the role of these mutations in vivo, we generated a knock-in mouse with the Gabrb3(D120N) mutation (Gabrb3+/D120N). I found that Gabrb3+/D120N mice had early onset epileptic spasms from P14-P17 and multiple types of seizures in adulthood including typical and atypical absence, myoclonic, tonic, and generalized tonic-clonic seizures. The predominant seizure type in adult Gabrb3+/D120N mice were absence seizures (~400/day), which are the characteristic seizures of LGS. The gabrb3+/D120N mouse is the first mouse model of LGS and the first mouse model with spontaneous atypical absence seizures and LGS behavioral comorbidities. Gabrb3+/D120N mice will aid in understanding the pathophysiology and treatment of LGS.
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