The Girk2 ( wv ) (weaver) mutation impairs migration of cerebellar granule cells from external to internal granular layer and induces neuronal death during the first 2 weeks of postnatal life. Kainate receptors are heteromeric ionotropic receptors of glutamate consisting of five subunits termed GluR5, GluR6, GluR7, KA1 and KA2. In order to investigate whether the weaver gene affects the expression of kainate receptors in weaver cerebellum, we determined mRNA expression levels of GluR6 kainate receptor subunit and [(3)H]kainic acid specific binding in the developing cerebellum, using in situ hybridization and receptor film autoradiography, respectively. In the weaver postnatal day 10 (P10) cerebellum, our data indicated lower levels of GluR6 mRNA expression and lower [(3)H]kainic acid specific binding in external granular layer (EGL) compared to normal EGL. Our results are indicative of either down-regulation of kainate receptors or modulation of their functional characteristics in weaver granule cells.
The weaver mutant mouse is characterized by degeneration of the dopaminergic mesencephalic neurons. The role of the dopaminergic system in the regulation of N-methyl-d-aspartate (NMDA) receptor subunit expression was addressed in the present study. In situ hybridization experiments were conducted to determine the expression levels of the NMDA receptor subunit mRNAs, z1, epsilon1 and epsilon2, in striatum, nucleus accumbens, olfactory tubercle and cerebral cortical regions of 26-day-, 3- and 6-month-old weaver mice. Data indicated statistically significant increases in z1 and epsilon2 mRNA levels in 6-month-old weaver striatum, whereas at the same age epsilon1 mRNA expression was decreased in all striatal regions, as well as in the cortex. In the 26-day-old weaver striatum and nucleus accumbens, statistically significant increases were observed in epsilon1 mRNA levels, whereas no changes were observed in the other two subunits. In the somatosensory cortex of 26-day-old weaver brain an increased expression of all three subunits was observed. The upregulation of NMDA receptor subunit expression observed in the somatosensory cortex can be attributed to a decreased activity of the glutamatergic thalamocortical pathway, following the degeneration of the nigrostriatal dopaminergic fibres. In the striatum, the present results demonstrate a differential control on the expression of z1 and epsilon2 subunits on the one hand, and epsilon1 subunit on the other. It is suggested that dopamine exerts a negative control on the expression of z1 and epsilon2 subunits, through a downregulation of transcription factors associated with the AP1 regulatory site, which is mediated by the activation of striatal dopamine D2 receptors.
The expression of AMPA receptor subunit mRNAs and the binding of [(3)H]AMPA were studied in the cerebellum of normal and "Purkinje cell degeneration" ( pcd) mutant mouse. In the pcd cerebellum, [(3)H]AMPA binding was decreased significantly in both the molecular and granule cell layers by 63% and 36%, respectively. In those mutants, GluRA, GluRB and GluRC mRNAs were not detected in the Purkinje cell layer, and the levels of GluRB and GluRD mRNAs were significantly decreased in the granule cell layer by 16% and 57%, respectively. Cerebellar grafts transplanted into the pcd cerebellum expressed only GluRB and GluRC mRNAs, suggesting that donor cells express the appropriate subunits normally expressed by Purkinje neurons. Our results, firstly, support the idea that the expression of the GluRA subunit in Golgi epithelial cells may depend upon the sustained interaction with adjacent Purkinje cells, and secondly, suggest that granule cells which are more resistant to transsynaptic death may express higher levels of GluRB mRNA.
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