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Volume 17, Number 7, Issue of April 1, 1997 pp. 2391-2399
Copyright ©1997 Society for Neuroscience

Expression of the GABA_A Receptor  Subunit Is Selectively Modulated by Depolarization in Cultured Rat Cerebellar Granule Neurons

Received Oct. 29, 1996; revised Jan. 16, 1997; accepted Jan. 21, 1997.

Laura M. Gault¹ and Ruth E. Siegel²

¹ Departments of Neurosciences and ² Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4965

The levels of several GABA_A receptor subunit mRNAs increase as cerebellar granule neurons migrate to their adult positions and receive excitatory mossy fiber input. Despite the temporal similarity of these increases in transcript expression in vivo, studies in cultured granule neurons demonstrated that the subunit mRNAs are differentially regulated. To address the possibility that neuronal activity regulates transcript expression, GABA_A receptor subunit mRNA levels were assessed in cultured granule neurons grown in chemically defined, serum-free medium containing either nondepolarizing (5 mM) or depolarizing (25 mM) KCl concentrations. Whereas the  subunit mRNA was almost undetectable in cultures maintained in nondepolarizing medium, an eightfold increase occurred between days 2 and 4 in cultures grown in depolarizing medium. Furthermore,  subunit transcript expression was reduced by 76 ± 6% when neurons in depolarizing medium were switched into nondepolarizing medium. The importance of depolarization in the initiation and maintenance of subunit transcript expression in granule neurons was selective for the GABA_A receptor  subunit. These changes in transcript expression involved calcium entry through L-type calcium channels. Nifedipine treatment (1 µM) both reduced intracellular calcium and decreased  subunit mRNA expression by 79 ± 4%. Furthermore, inhibition of Ca²⁺/calmodulin-dependent protein kinases (CaM kinases) by KN-62 (1 µM) also reduced  subunit transcript expression. These studies demonstrate that KCl-induced depolarization, a condition that mimics the effects of neuronal activity, selectively modulates GABA_A receptor  subunit mRNA expression through a pathway involving calcium entry and activation of a CaM kinase.

Key words: GABA_A receptor; receptor subunit mRNAs; rat cerebellar granule neurons; membrane depolarization; neuronal activity; calcium influx; Ca²⁺/calmodulin-dependent protein kinase (CaM kinase)

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