Suppression of neuronal hyperexcitability and associated delayed neuronal death by adenoviral expression of GABA(C) receptors.

Published

Journal Article

The excessive neuronal excitation underlying several clinically important diseases is often treated with GABA allosteric modulators in an attempt to enhance inhibition. An alternative strategy would be to enhance directly the sensitivity of postsynaptic neurons to GABA. The GABA(C) receptor, normally found only in the retina, is more sensitive to GABA and demonstrates little desensitization compared with the GABA(A) receptor. We constructed an adenovirus vector that expressed cDNA for both the GABA(C) receptor rho(1) subunit and a green fluorescent protein (GFP) reporter and used it to transduce cultured hippocampal neurons. Transduced neurons were identified by fluorescence, double immunocytochemistry proved colocalization of the rho(1) protein and the reporter, Western blot verified the expected molecular masses, and electrophysiological and pharmacological properties confirmed the presence of functional GABA(C) receptors. rho(1)-GFP transduction resulted in an increased density of GABA(A) receptors as well as expression of novel GABA(C) receptors. This effect was not reproduced by addition of TTX or Mg(2+) to the culture medium to reduce action potentials or synaptic activity. In a model of neuronal hyperexcitability induced by chronic blockade of glutamate receptors, expression of GABA(C) receptors abolished the hyperactivity and the consequent delayed neuronal death. Adenovirus-mediated neuronal GABA(C) receptor engineering, via its dual mechanism of inhibition, may offer a way of inhibiting only those hyperexcitable neurons responsible for clinical problems, avoiding the generalized nervous system depression associated with pharmacological therapy.

Full Text

Duke Authors

Cited Authors

  • Cheng, Q; Kulli, JC; Yang, J

Published Date

  • May 15, 2001

Published In

Volume / Issue

  • 21 / 10

Start / End Page

  • 3419 - 3428

PubMed ID

  • 11331372

Pubmed Central ID

  • 11331372

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Language

  • eng

Conference Location

  • United States