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The Journal of Neuroscience, May 24, 2006, 26(21):5673-5683; doi:10.1523/JNEUROSCI.0860-06.2006

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Development/Plasticity/Repair
Transcriptional Signatures of Cellular Plasticity in Mice Lacking the 1 Subunit of GABA_A Receptors

Igor Ponomarev,¹ Rajani Maiya,¹ Mark T. Harnett,¹ Gwen L. Schafer,¹ Andrey E. Ryabinin,² Yuri A. Blednov,¹ Hitoshi Morikawa,¹ Stephen L. Boehm, II,³ Gregg E. Homanics,⁴ Ari Berman,¹ Kerrie H. Lodowski,¹ Susan E. Bergeson,¹ and R. Adron Harris¹

¹Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas 78712, ²Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239, ³Department of Psychology, State University of New York at Binghamton, Binghamton, New York 13902, and ⁴Departments of Anesthesiology and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Correspondence should be addressed to Igor Ponomarev, Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712. Email: piatut{at}mail.utexas.edu

GABA_A receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the 1 subunit of GABA_A receptors results in a loss of 1-mediated fast inhibitory currents and a marked reduction in density of GABA_A receptors. A grossly normal phenotype of 1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of 1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel 4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of 1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in 1 null mutants.

Key words: knock-out; null mutant; microarray; gene expression; neuroadaptation; synapse; neuron; glia

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Received Oct. 4, 2005; revised March 31, 2006; accepted April 1, 2006.

Correspondence should be addressed to Igor Ponomarev, Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712. Email: piatut{at}mail.utexas.edu

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