Impairment of AMPA Receptor Function in Cerebellar Granule Cells of Ataxic Mutant MouseStargazer

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Abstract
The spontaneous recessive mutant mousestargazer(stg) begins to show ataxia around postnatal day 14 and display a severe impairment in the acquisition of classical eyeblink conditioning in adulthood. These abnormalities have been attributed to the specific reduction in brain-derived neurotrophic factor (BDNF) and the subsequent defect in TrkB receptor signaling in cerebellar granule cells (GCs). In thestgmutant cerebellum, we found that EPSCs at mossy fiber (MF) to GC synapses are devoid of the fast component mediated by AMPA-type glutamate receptors despite the normal slow component mediated by NMDA receptors. The sensitivity ofstgmutant GCs to exogenously applied AMPA was greatly reduced, whereas that to NMDA was unchanged. Glutamate release from MF terminals during synaptic transmission to GCs appeared normal. By contrast, AMPA receptor-mediated EPSCs were normal in CA1 pyramidal cells of thestgmutant hippocampus. Thus, postsynaptic AMPA receptor function was selectively impaired instgmutant GCs, although the transcription of four AMPA receptor subunit genes in thestgGC was comparable to the wild-type GC. We also examined the cerebellum of BDNF knockout mice and found that their MF–GC synapses had a normal AMPA receptor-mediated EPSC component. Thus, the impaired AMPA receptor function in thestgmutant GC is not likely to result from the reduced BDNF–TrkB signaling. These results suggest that the defect in MF to GC synaptic transmission is a major factor that causes the cerebellar dysfunction in thestgmutant mouse.