Metabotropic glutamate receptors and cell-type-specific vulnerability in the striatum: Implication for ischemia and Huntington's disease

Differential sensitivity to glutamate has been proposed to contribute to th e cell-type-specific vulnerability observed in neurological disorders affec ting the striatum such as Huntington's disease (HD) and global ischemia. Un der these pathological conditions striatal spiny neurons are selectively lo st while large aspiny (LA) cholinergic interneurons are spared. We studied the electrophysiological effects of metabotropic glutamate receptor (mGluR) activation in striatal spiny neurons and LA interneurons in order to defin e the role of these receptors in the pathophysiology of the striatum. DCG-I V and L-SOP, agonists for group II and III mGluRs respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory s ynaptic potentials in both spiny neurons and LA interneurons. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no detectable ef fects on membrane properties and glutamatergic synaptic transmission in spi ny neurons while it caused a slow membrane depolarization in LA interneuron s coupled to increased input resistance. In combined electrophysiological a nd microfluorometric recordings, 3,5-DHPG strongly enhanced membrane depola rizations and intracellular Ca2+ accumulation induced by MMDA applications in spiny neurons but not in LA interneurons. Activation of protein kinase C (PKC) by phorbol 12,13-diacetate mimicked this latter action of 3,5-DHPG w hile the facilitatory effect of 3,5-DHPG was prevented by calphostin C, an inhibitor of PKC. These data indicate that a positive interaction between N MDA receptors and group I mGluRs, via PKC activation, is differently expres sed in these two neuronal subtypes. Our data also suggest that differential effects of the activation of group I mGluRs, but not of group II and III m GluRs, might partially account for the selective vulnerability to excitotox ic damage observed within the striatum. (C) 1999 Academic Press.