| Research Abstract |
To examine the roles of diverse glutamate receptor (GluR) channel subunits in the brain function, we generated mutant mice defective in respective subunits. The disruption of the GluRepsilon1 subunit of the NMDA-type GluR channel results in the decrease of functional NMDA receptor channels and the increase of the threshold for long-term potentiation induction. The GluRepsilon1 subunit mutant mice with highly homogenous genetic background show poor contextual fear conditioning under weak conditional stimuli due to the increased threshold for the contextual learning. These results suggest that synaptic plasticity is the cellular basis of a certain form of learning and memory. The GluRepsilon2 subunit mutation hindered the formation of the whisker-related neuronal barrelette structure in the brainstem trigeminal nucleus and synaptic plasticity in the hippocampus. Thus, the GluRepsilon2 subunit of the NMDA receptor channel plays important roles in both synapse refinement during development and synaptic plasticity. The GluRdelta2 subunit of the GluR channel is selectively localized in cerebellar Purkinje cells. Analyses of the GluRdelta2 mutant mice reveal that the GluRdelta2 subunit plays roles in motor coordination, motor learning and cerebellar long-term depression. Furthermore, the GluRdelta2 mutant mice show the reduced stability of parallel fiber-Purkinje cell synapses and impairment of elimination of multiple climbing fibers during development. These results suggest that the GluRdelta2 subunit is essential in cerebellar synaptic plasticity, motor learning and Purkinje cell synapse formation. Our results suggest that some of the GluR channels play important roles in neural network formation during brain development and in higher brain function, implying that these processes share common molecular mechanisms.
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