Metabotropic Glutamate Receptors and Neuronal Toxicity

Abstract

Specific glutamate receptors coupled to polyphosphoinositide (PPI) hydrolysis have been described in brain slices, cultured neurons, and astrocytes, and in amphibian oocytes injected with rat brain mRNA (Sladeczek et al., 1985; Nicoletti et al., 1986a,b; Sugiyama et al., 1987). In most of the systems, metabotropic receptors are activated by lS,3R-aminocyclopentandicarboxylic acid (ACPD), quisqualate, ibotenate, and L-glutamate, but not by α-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) (Nicoletti et al., 1986a; Schoepp and Johnson, 1988; 1989; Palmer et al., 1989). Trans-ACPD has been described as the most selective agonist of metabotropic receptors (Palmer et al., 1989), although it is less potent than quisqualate in stimulating inositolphosphate formation. In brain slices, stimulation of PPI hydrolysis by metabotropic receptor agonists is extremely high at the earlier stages of postnatal development (within the first 2 weeks after birth) and progressively declines during maturation (Nicoletti et al., 1986a). In adult tissue, the activation of metabotropic receptors is amplified in response to deafferentation (Nicoletti et al., 1987), as well as after induction of long-term potentiation (Aronica et al., 1991) or electrical kindling (Iadarola et al, 1986; Akiyama et al., 1987). Hence, it is likely that metabotropic receptors contribute to the synaptic events involved in the regulation of neuronal plasticity. However, based on the toxic effects of quisqualate in hippocampal slices (Garthwaite and Garthwaite, 1989) and cultured cortical neurons (Patel et al., 1990), a role for metabotropic receptors in the mechanism of neuronal degeneration has been suggested. We have addressed this problem in primary cultures of cerebellar neurons.