GABAA α6-Containing Receptors Are Selectively Compromised in Cerebellar Granule Cells of the Ataxic Mouse, Stargazer

Abstract

Stargazer mice fail to express the ␥2 isoform of transmembrane ␣-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor regulatory proteins that has been shown to be absolutely required for the trafficking and synaptic targeting of excitatory AMPA receptors in adult murine cerebellar granule cells. Here we show that 30 ؎ 6% fewer inhibitory ␥-aminobutyric acid, type A (GABA A ), receptors were expressed in adult stargazer cerebellum compared with controls because of a specific loss of GABA A receptor expression in the cerebellar granule cell layer. Radioligand binding assays allied to in situ immunogold-EM analysis and furosemide-sensitive tonic current estimates revealed that expression of the extrasynaptic (␣6␤x␦) ␣6-containing GABA A receptor were markedly and selectively reduced in stargazer. These observations were compatible with a marked reduction in expression of GABA A receptor ␣6, ␦ (mature cerebellar granule cell-specific proteins), and ␤3 subunit expression in stargazer. The subunit composition of the residual ␣6-containing GABA A receptors was unaffected by the stargazer mutation. However, we did find evidence of an ϳ4-fold up-regulation of ␣1␤␦ receptors that may compensate for the loss of ␣6-containing GABA A receptors. PCR analysis identified a dramatic reduction in the steady-state level of ␣6 mRNA, compatible with ␣6 being the primary target of the stargazer mutation-mediated GABA A receptor abnormalities. We propose that some aspects of assembly, trafficking, targeting, and/or expression of extrasynaptic ␣6-containing GABA A receptors in cerebellar granule cells are selectively regulated by AMPA receptor-mediated signaling.

Cerebellar defects in a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Many of these mutant models show a selective loss of subclasses of cells within the cerebellum, including a selective loss of both Purkinje and granule cells in the RORα mutant-staggerer mutant (Doulazmi et al, 2006; Vogel et al, 2000), the lurcher (McFarland et al, 2007), scrambler (Goldowitz et al, 1997; Yang et al, 2002), and reeler (Badea et al, 2007) mutants. Other cerebellar mutant mice, such as the stargazer mutants, show only molecular changes, with minimal cell loss (Payne et al, 2007). Mechanistically, these models have provided insight into deficits in cell migration, proliferation, and atrophy due to loss of tropic support.…”

Vitamin C Deficiency Causes Severe Defects in the Development of the Neonatal Cerebellum and in the Motor Behaviors ofGulo−/−Mice

“…S6). GABRA6 is a mature cerebellar granule cell-specific protein and its expression is downregulated in the ataxic mouse, Stargazer (47). Interestingly, BDNF induces the expression of granule neuron terminal differentiation markers, particularly GABRA6 mRNA, to regulate the maturation of developing cerebellar granule neurons (4).…”

Perinatal intermittent hypoxia alters γ‐aminobutyric acid: a receptor levels in rat cerebellum

“…Approximately 45% of GABA A receptors extracted from cerebellar extracts of adult rats contain α6 subunits coupled with other subunits, including α1, β1, β2, β3, γ2, and δ as such α6βxγ2, α1α6βxγ2, α6βxδ, or α1α6βxδ (Jechlinger et al, 1998). Although α6 subunit knockout mice reveal no clear phenotypic abnormalities, stargazer mice that lack α6 subunits in the cerebellum show ataxia (Payne et al, 2007). In stargazer mice, α6 and δ subunit expressions are reduced by approximately 50% or more of controls.…”