Vol. 291, Issue 1, 361-366, October 1999

Zinc Inhibition of -Aminobutyric Acid_A Receptor Function Is Decreased in the Cerebral Cortex during Pilocarpine-Induced Status Epilepticus¹

Pradeep K. Banerjee, Richard W. Olsen and O. Carter Snead, III

Department of Pharmacology, the Brain Research Institute (P.K.B., R.W.O.), and the Molecular Biology Institute (R.W.O.), University of California, Los Angeles, California; Division of Neurology, the Brain and Behavior Program, Hospital for Sick Children, and Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (O.C.S.)

Functional modulation of -aminobutyric acid_A (GABA_A) receptors by Zn²⁺, pentobarbital, neuroactive steroid alphaxalone, and flunitrazepam was studied in the cerebral cortex and cerebellum of rats undergoing status epilepticus induced by pilocarpine. Under control conditions, Zn²⁺ dose-dependently inhibited muscimol-stimulated uptake of ³⁶Cl in cortical and cerebellar membranes. However, Zn²⁺ inhibition of stimulated ³⁶Cl uptake was selectively decreased in the cortex (but not in the cerebellum) 1 to 2 h after the onset of status epilepticus. This loss of Zn²⁺ response in the cortex appeared to be selective to Zn²⁺ only, because pentobarbital-, alphaxalone-, or flunitrazepam enhancement of muscimol-stimulated ³⁶Cl uptake did not change in this brain region either at 1 or 2 h after seizures. Because this loss of Zn²⁺ response in the cortex was apparent only about 1 h after the onset of status epilepticus but not earlier, we tested whether status epilepticus was critical for the development of the loss of Zn²⁺ response. We found that, in rats where status epilepticus was terminated by diazepam within 30 min after seizure onset, Zn²⁺ response was preserved in the cortex. These findings suggest that continuous seizures of pilocarpine-induced status epilepticus caused a rapid and selective decrease in Zn²⁺ inhibition of GABA_A receptor function in the cortex. The possible relevance of such rapid seizure-induced GABA_A receptor plasticity in the cerebral cortex is discussed.