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The Journal of Neuroscience, April 15, 1998, 18(8):2822-2833

Mouse Cerebellar Granule Cell Differentiation: Electrical Activity Regulates the GABA_A Receptor 6 Subunit Gene

J. R. Mellor, D. Merlo, A. Jones, W. Wisden, and A. D. Randall

Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 2QH, United Kingdom

GABA_A receptor 6 subunit gene expression marks cerebellar granule cell maturation. To study this process, we used the 6lacZ mouse line, which has a lacZ reporter inserted into the 6 gene. At early stages of postnatal cerebellar development, 6-lacZ expression is mosaic; expression starts at postnatal day 5 in lobules 9 and 10, and 6-lacZ is switched on inside-out, appearing first in the deepest postmigratory granule cells. We looked for factors regulating this expression in cell culture. Membrane depolarization correlates inversely with 6-lacZ expression: granule cells grown in 25 mM [K⁺]_o for 11-15 d do not express the 6 gene, whereas cultures grown for the same period in 5 mM [K⁺]_o do. This is influenced by a critical early period: culturing for 3 d in 25 mM [K⁺]_o curtails the ability to induce the 6 gene on transfer to 5 mM [K⁺]_o. If the cells start in 5 mM [K⁺]_o, however, they still express the 6-lacZ gene in 25 mM [K⁺]_o. In contrast to granule cells grown in 5 mM [K⁺]_o, cells cultured in 25 mM [K⁺]_o exhibit no action potentials, mEPSCs, or mIPSCs. In chronic 5 mM [K⁺]_o, factors may therefore be released that induce 6. Blockade of ionotropic and metabotropic GABA and glutamate receptors or L-, N-, and P/Q-type Ca²⁺ channels did not prevent 6-lacZ expression, but inhibition of action potentials with tetrodotoxin blocked expression in a subpopulation of cells.

Key words: GABA_A receptor subunit; cerebellum; granule cell; -galactosidase reporter genes; internal ribosome entry site; differentiation; cell culture; electrophysiology; transgenic mice; membrane depolarization; action potentials; tetrodotoxin; neuron-specific gene expression

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1882822-12$05.00/0

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