Physiological analysis of Rasmussen's encephalitis: patch clamp recordings of altered inhibitory neurotransmitter function in resected frontal cortical tissue

Gibbs III, John W; Morton, Lawrence D; Amaker, Barbara; Ward, John D; Holloway, Kathryn L; Coulter, Douglas A

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Volume 31, Issue 1 , Pages 13-27, June 1998

Physiological analysis of Rasmussen's encephalitis: patch clamp recordings of altered inhibitory neurotransmitter function in resected frontal cortical tissue

John W Gibbs III
- Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0599, USA
Lawrence D Morton
- Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, PO Box 980599, Richmond, VA 23298-0599, USA
- MCV Comprehensive Epilepsy Institute of Virginia Commonwealth University, Richmond, VA 23298-0599, USA
Barbara Amaker
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0599, USA
John D Ward
- Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0599, USA
- MCV Comprehensive Epilepsy Institute of Virginia Commonwealth University, Richmond, VA 23298-0599, USA
Kathryn L Holloway
- Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0599, USA
- MCV Comprehensive Epilepsy Institute of Virginia Commonwealth University, Richmond, VA 23298-0599, USA
Douglas A Coulter
- Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, PO Box 980599, Richmond, VA 23298-0599, USA
- Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0599, USA
- MCV Comprehensive Epilepsy Institute of Virginia Commonwealth University, Richmond, VA 23298-0599, USA
- Corresponding author. Tel.: +1 804 8283391; fax: +1 804 8286373; e-mail: dcoulter@gems.vcu.edu

Received 14 October 1997; received in revised form 17 December 1997; accepted 13 February 1998.

Abstract

Rasmussen's encephalitis (RE) is a progressive, rare childhood disease characterized by severe epilepsy, hemiplegia, dementia, and inflammation of the brain. While one mechanism underlying the pathogenesis of RE has been hypothesized to be mediated by production of excitotoxic GluR3 autoantibodies to the AMPA receptor, other neuropathological etiologies have also been indicated. Whole-cell patch clamp recordings of GABA_A receptor mediated responses were conducted in neurons acutely isolated from an RE patient, and compared to properties of non-focal human temporal cortical neurons. RE neurons appeared similar anatomically to control cortical neurons. Significant differences in GABAergic responses were evident between RE and control neurons. GABA was significantly more potent in RE than in control cortical neurons (EC₅₀ of 13 μM vs 23 μM, respectively). In addition, the overall efficacy of GABA was significantly decreased in RE neurons, associated with a decrease in postsynaptic GABA current density in RE neurons (5.1 pA/μm²) in comparison to controls (9.2 pA/μm²). Augmentation of GABA responses by the benzodiazepine, clonazepam (CNZ), was significantly reduced in RE in comparison to control neurons (34% vs 99% augmentation at 100 nM). The RE-associated reduced functional efficacy and altered pharmacology of neuronal GABA_A receptors is consistent with overall disinhibition in RE neurons, and could contribute to the generation of the severe epileptic activity evident in this disorder.

Keywords: GABA_A receptor, Whole-cell patch clamp, Benzodiazepine, Epilepsy, Rasmussen's encephalitis