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The Journal of Neuroscience, July 15, 1999, 19(14):6027-6036
Impairment of AMPA Receptor Function in Cerebellar Granule Cells of Ataxic Mutant Mouse Stargazer
Kouichi Hashimoto1, 2, 3, Masahiro Fukaya4, Xiaoxi Qiao5, Kenji Sakimura6, Masahiko Watanabe4, and Masanobu Kano2, 3 1 Department of Physiology, Jichi Medical School, Minamikawachi-machi, Tochigi-ken 329-0498, Japan, 2 Department of Physiology, Kanazawa University School of Medicine, Takara-machi, Kanazawa 920-8640, Japan, 3 CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan, 4 Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan, 5 Program for Neural, Informational, and Behavioral Sciences, University of Southern California, Los Angeles, California 90089, and 6 Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan
The spontaneous recessive mutant mouse stargazer (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 the stg mutant 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 of stg mutant 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 the stg mutant hippocampus. Thus, postsynaptic AMPA receptor function was selectively impaired in stg mutant GCs, although the transcription of four AMPA receptor subunit genes in the stg GC 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 the stg mutant 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 the stg mutant mouse.
Key words: mutant mouse; ataxia; stargazer; cerebellum; AMPA receptor; granule cell; mossy fiber; synaptic transmission; BDNF
Copyright © 1999 Society for Neuroscience 0270-6474/99/19146027-10$05.00/0
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