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The Journal of Neuroscience, May 15, 2001, 21(10):3419-3428

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_C Receptors

Qing Cheng¹, John C. Kulli², and Jay Yang^{1, 2}

Departments of ¹ Pharmacology and Physiology and ² Anesthesiology, University of Rochester Medical Center, Rochester, New York 14642

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 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 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. 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 Mg²⁺ 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.

Key words: GABA_C receptors; hippocampal neurons; adenovirus; hyperexcitability; cell culture; delayed neuronal death

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21103419-10$05.00/0

This article has been cited by other articles:

				J. Yang, Q. Cheng, A. Takahashi, and F. Goubaeva Kinetic Properties of GABA {rho}1 Homomeric Receptors Expressed in HEK293 Cells Biophys. J., September 15, 2006; 91(6): 2155 - 2162. [Abstract] [Full Text] [PDF]

				Q. Cheng, P. M. Burkat, J. C. Kulli, and J. Yang GABACrho 1 Subunits Form Functional Receptors But Not Functional Synapses in Hippocampal Neurons J Neurophysiol, November 1, 2001; 86(5): 2605 - 2615. [Abstract] [Full Text] [PDF]

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