Transcriptional Signatures of Cellular Plasticity in Mice Lacking the α1 Subunit of GABA_AReceptors

Abstract

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.

Distinct Regulation of β2 and β3 Subunit-Containing Cerebellar Synaptic GABAAReceptors by Calcium/Calmodulin-Dependent Protein Kinase II

“…Although compensatory changes to the expression levels of other ␤ subunits might occur after removing the ␤2 subunit (Ponomarev et al, 2006), it seems unlikely that ␤1 subunit expression is increased because its expression is at best minimal in CGCs (Laurie et al, 1992;Pirker et al, 2000), which we confirmed in our ␤2 appear to be modulated by ␣-CaMK-II. This contrasts with the lack of modulation by ␣-CaMK-II of recombinant ␣1␤2␥2S receptors expressed in NG108-15 cells (Houston and Smart, 2006), which implies that the neuronal inhibitory synaptic environment is vitally important for supporting ␣-CaMK-II modulation of GABA A receptor isoforms.…”

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…66 Furthermore, a targeted deletion of the GABA A receptor a1 subunit gene in mice resulted in altered cortical expression of other GABA A receptor subunits, such as increased a2 and decreased g2 protein levels, as well as decreased levels of SST mRNA. 67,68 Together, these findings suggest that the deficit in a1 subunit expression could be an upstream event to other GABA-related gene expression changes in the DLPFC of subjects with schizophrenia.…”

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

“…One of the problems in interpretation of results obtained with knockout mice is whether compensatory changes in expression of other genes occur as a result of deletion of particular gene (Ponomarev et al, 2006). Although this issue…”