What is normal, anyway? Mice lacking the 1 subunit of the GABA_A receptor surprisingly show no overt phenotypic differences from their wild-type littermates. Is this protein, which is an integral component of most GABA receptors, therefore unimportant in GABAergic neurotransmission? Ponomarev et al. suggest the opposite, reporting dynamic changes in genes involved in neuronal excitability in GABA_A 1 knockout mice using cDNA microarrays and localization data from publicly available databases, including the Allen Brain Atlas, in a recent article in the Journal of Neuroscience.

Image of GABAA α1 expression
from the Allen Brain Atlas. The
image is coded by an expression
filter in which red indicates high
and blue indicates low levels of
gene expression.

The authors identified 982 genes differentially expressed in the knockout and wild-type cortex and cerebellum, many of which are involved in GABA and glutamate neurotransmission. Abat , Got2 and Glud1 , which contribute to glutamate and GABA metabolism, were upregulated in the knockout relative to the wild-type cerebellum. The authors also found increased expression in the knockout cerebellum of the AMPA3 glutamate receptor ( Gria3 ), the metabotropic glutamate receptor mGluR2 ( Grm2 ) and the vesicular transporter VGLUT2 ( Slc17a6 ). In contrast, they found diminished expression in the knockout cerebellum of mGlur7 (Grm7), mGlur8 (Grm8) and collybistin ( Arhgef9 ), which is involved in GABA receptor clustering. The authors therefore suggest that in the knockout, the cerebellum undergoes homeostatic changes to compensate for the loss of GABA_A 1.

Using the Allen Brian Atlas, the authors identified the cell-specific localization of differentially regulated genes in the cerebellum. The knockout showed diminished cerebellar expression of the sodium channel 4 subunit ( Scn4b ) and the potassium voltage-gated Kv4.2 channel ( Kcnd2 ), which help mediate high-frequency neuronal firing, but localize predominantly to Purkinje and granule cells, respectively. The authors suggest that these similar genetic alterations help compensate for the compromised inhibitory tone in independent cell populations in the knockout. The knockout also showed increased cerebellar expression of glutamate dehydrogenase 1 (Glud1) and serine racemase (Srr), which localize predominantly to Bergman glia, supporting a role for glia in regulating neuronal excitability.

Using the Mouse Neuronal Expression Database, which profiles gene expression of 12 populations of neurons, the authors localized differentially expressed cortical genes to GABAergic and glutamatergic cell populations. On the whole, they found increased gene expression in glutamatergic cells, and the frequency of gene-expression changes within a cell population correlated with its endogenous expression of GABA_A 1. Differentially regulated genes in the knockout and wild-type cortex included Vamp1 , Syn2 and Vat1 , which are involved in vesicular release and localize predominantly to GABAergic cells. The knockout also showed decreased cortical expression of Rac1 , a small GTPase involved in dendritic spine formation that localizes to glutamatergic cells.

Together, these data suggest a shift in the balance of excitatory and inhibitory neurotransmitter systems in the GABA_A 1 knockout mouse. The authors found mostly distinct functional themes and pathways represented by the differentially expressed genes in GABAergic and glutamatergic cells of the cortex and Purkinje and granule cells of the cerebellum, suggesting that discrete populations of neurons use different tactics to compensate for shifts in the balance of excitatory and inhibitory neurotransmitters.

1. Ponomarev., I. et al. Transcriptional signatures of cellular plasticity in mice lacking the 1 subunit of GABA_A receptors. Journal of Neuroscience. 26, 5673– 5683 (2006)  | Article |