Three different mutant mouse strains, spastic, spastic-allele and spastic-like have indistinguishable behavioral abnormalities: tremor, toe walking gait, and loss of righting reflex. These behavioral abnormalities can be reproduced in normal mice given subconvulsive doses of the glycine receptor antagonist strychnine. This result suggests that all three mutants have a defect in glycine mediated inhibition. The spastic and spastic-allele mutants have an 80 and 95% loss of strychnine binding sites in the CNS suggesting that there is a large reduction in postsynaptic glycine receptors. On the other hand, the spastic-like mutant has control levels of strychnine binding suggesting that the behavioral abnormalities are produced by a defect in some other aspect of glycine mediated inhibition. In effected regions of the spastic CNS, there is also increased binding to the GABA and benzodiazepine receptors, and increased accumulation of glycine and GABA. These results suggest that there is an increase in other aspects of the glycine synaptic system, and the other major inhibitory neurotransmitter in brain, GABA. The purpose of the research proposed in this application is to further define the nature or the abnormalities in these three mutants in order to better understand the glycine neurotransmitter system and its interrelationships with other CNS neurotransmitter systems. Specific experiments will include detailed investigations into the uptake, release, content, and metabolism of glycine to determine the involvement of presynaptic measures of glycine synaptic function in the expression of these mutations. Spinal cord neurons from mutant animals will be grown in cell culture to determine if the abnormalities are expressed in vitro. Intracellular physiological experiments will be performed to determine if there are any alterations in either the passive or active electrical properties of cultured mutant neurons. More importantly, these studies will investigate the physiological consequences of the reduction in strychnine binding sites by measuring glycine and strychnine sensitivity. These studies and further biochemical studies will attempt to determine the relationship between the strychnine binding site and the glycine recognition site of the postsynaptic glycine receptor. The gene dosage, developmental, and regional localization of any alterations found in the glycine system will also be studied and potential compensatory changes will be sought in other neurotransmitter systems.
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