Binding, uptake, and release of L-glutamate and related compounds in the brain : comparisons between DBA and C57 mice.

L-Glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system (CNS), is involved in many physiological processes and some neurological disorders including epilepsy. The DBA/2J (DBA) and C57 BL/6J (C57) mice are used to study the mechanisms of epileptogenesis. Glutamate and related excitatory amino acids (EAAs) are potent convulsants. Compared with the C57 mice, the DBA mice show higher susceptibility to the convulsive effects of EAAs. Experimental evidence suggests that the higher susceptibility of DBA mice to audiogenic and electroshock seizures is mediated largely by the glutamatergic transmission system. However, little is known about the underlying mechanism. Fundamental issues such as whether and at what loci abnormalities in central glutamatergic transmission exist are still not fully understood. Theoretically, higher EAA receptor density in postsynaptic neurons, increased EAA concentration in the synaptic cleft as the result of impaired EAA uptake and excessive EAA release are potential mechanisms underlying excessive glutamatergic excitation. The possible role of EAAs in epileptogenesis in DBA mice was investigated in this study. In Chapter 1, the characteristics of binding of agonist and antagonists of glutamate receptors to membranes prepared from DBA and C57 mice are reported. Chapter 2 and Chapter 3 cover the characterization of the respective process of EAA release from and uptake by cultured astrocytes, synaptosomes, and brain slices derived from DBA and C57 mice. The major findings from the binding studies indicate that glutamate and CNQX high affinity binding site densities are significantly higher in the cortex of 3-week-old DBA, compared with C57 mice. These indicate that increased cortical non-NMDA receptor density may contribute to higher seizure susceptibility or more marked seizure severity in 3-week-old DBA mice. Results from the release studies show that the extent of release of glutamate and aspartate were not significantly different between preparations from DBA and C57 mice, suggesting that the higher seizure susceptibility of DBA mice is probably not attributable to enhanced EAA release. Result from the uptake studies does not suggest the existence of an impairment of EAA uptake in brains of 3-week-old DBA mice.