Synaptic localization of kainic acid binding sites

The heterocyclic compound kainic acid (KA) is a potent excitant when applied to mammalian neurones. Lesions caused by injections of KA into the rat striatum and hippocampus cause similar patterns of damage to those seen in Huntington's chorea and status epilepticus, respectively. Although it was originally thought to be a glutamate agonist, it is now clear that KA does not act on the majority of the receptors for glutamate, and in fact seems to act on a class of receptors which are distinct from those which mediate responses to other excitatory amino acids. The potent and selective neurotoxic effects of this compound may be mediated by these same receptors. At present, the relative distribution of junctional and extrajunctional (non-synaptic) receptors is unknown and resolution of this issue would provide important insights into the action of KA on the central nervous system (CNS). We show here that KA binding sites are greatly enriched in isolated synaptic junctions from rat brain and, using an in vitro autoradiographic technique, we have found that these binding sites are concentrated specifically in terminal fields where KA acts as a potent neurotoxin.     

Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

Cutting the axons of the cholinergic neurons that project to the hippocampal formation results in death of most of these cells. Previous studies have shown that administration of nerve growth factor before or at the same time as the lesion will prevent this cell death. Here we demonstrate that basic fibroblast growth factor (FGF) administered into the brain reduces the death of cholinergic neurons in the medial septum and diagonal band of Broca after transection of their axons, in both young adult and aged rats. Moreover, FGF can partially protect against death of cholinergic neurons even when administered two days after axonal transection. These results indicate a possible function for FGF in the normal support of basal forebrain cholinergic neurons, but its range of activity could be wider, for FGF also supports noncholinergic neurons in vitro, it is localized in many of the central nervous system neurons, and it is found in relatively high concentrations in the brain.     

Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor

Protease nexin-II (PN-II) is a protease inhibitor that forms SDS-resistant inhibitory complexes with the epidermal growth factor (EGF)-binding protein, the gamma-subunit of nerve growth factor, and trypsin. The properties of PN-II indicate that it has a role in the regulation of certain proteases in the extracellular environment. Here we describe more of the amino-acid sequence of PN-II and its identity to the deduced sequence of the amyloid beta-protein precursor (APP). Amyloid beta-protein is present in neuritic plaques and cerebrovascular deposits in individuals with Alzheimer's disease and Down's syndrome. A monoclonal antibody against PN-II (designated mAbP2-1) recognized PN-II in immunoblots of serum-free culture medium from human glioblastoma cells and neuroblastoma cells, as well as in homogenates of normal and Alzheimer's disease brains. In addition, mAbP2-1 stained neuritic plaques in Alzheimer's disease brain. PN-II was a potent inhibitor of chymotrypsin with an inhibition constant Ki of 6 x 10(-10)M. Together, these data demonstrate that PN-II and APP are probably the same protein. The regulation of extracellular proteolysis by PN-II and the deposition of at least parts of the molecule in senile plaques is consistent with previous reports that implicate altered proteolysis in the pathogenesis of Alzheimer's disease.     

Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites

Glutamate is thought to serve as a major excitatory neurotransmitter throughout the central nervous system (CNS); electrophysiological studies indicate that its action is mediated by multiple receptors. Four receptors have been characterized by their selective sensitivity to N-methyl-D-aspartate (NMDA), kainic acid (KA), quisqualic acid (QA) and 2-amino-4-phosphonobutyric acid (APB). Electrophysiological evidence indicates that these receptors are all present in the rat hippocampus and that the anatomically discrete synaptic fields within the hippocampus exhibit differential sensitivity to the selective excitatory amino acid agents. Thus, we have used the hippocampus as a model system to investigate possible subpopulations of 3H-L-glutamate binding sites. By using quantitative autoradiography, the pharmacological specificity of 3H-L-glutamate binding in discrete terminal fields was determined. We report here that there are at least four distinct classes of 3H-L-glutamate binding sites which differ in their anatomical distribution, pharmacological profile and regulation by ions. Two of these sites seem to correspond to the KA and NMDA receptor classes, and a third site may represent the QA receptor. The fourth binding site does not conform to present receptor classifications. None of these binding sites corresponds to the major glutamate binding site observed in biochemical studies.     

Effect of antibrain synaptosomal fraction serum and complement on evoked potentials and impedance

Résumé L'introduction du «complément» (sérum de cobaye) dans le corps genouillé latéral du chat, produit une diminution des potentiels évoqués photiques et de l'impédance cérébrale. Ces effets sont prévenus par l'application locale d'un anti-serum réagissant spécifiquement avec les synaptosomes cérébraux.