DIFFERENTIAL INVOLVEMENT OF METABOTROPIC AND P75 NEUROTROPHIN RECEPTORS IN EFFECTS OF NERVE GROWTH-FACTOR AND NEUROTROPHIN-3 ON CULTURED PURKINJE-CELL SURVIVAL

We have examined the role of the p75 neurotrophin receptor in survival -promoting effects of nerve growth factor (NGF) and neurotrophin-3 (NT -3) on cultured Purkinje cells. Previously, we showed that NGF promote s Purkinje cell survival in conjunction with (1S,3R)-1-aminocyclopenta ne-1,3-dicarboxylic acid (ACPD), an agonist of metabotropic excitatory amino acid receptors, whereas NT-3 by itself increases cell number. W e now present evidence that p75 plays different roles in Purkinje cell responses to the two neurotrophins. A metabotropic receptor of the mG luR1 subtype may interact with p75 function, so as to regulate Purkinj e cell responsiveness Co neurotrophins. When cerebellar cultures were grown for 6 days in the presence of ACPD and a mutant form of NGF that does not bind to p75, no increase in Purkinje cell number was observe d. Moreover, the survival-promoting effect of wild-type NGF and ACPD c ould be inhibited by a neutralizing antiserum to p75 or by a pyrazoloq uinazolinone inhibitor of neurotrophin binding to p75. In contrast, th e response to NT-3 was potentiated by anti-p75 treatment and by the qu inazolinone. These data indicate the mediation of p75 in the trophic r esponse to NGF-ACPD and a negative modulatory role of p75 in the actio n of NT-3. To probe the role of ACPD in the p75-dependent response to NGF, metabotropic receptor subtype-specific ligands were tested. The p attern of agonist specificity implicated the mGluR1 subtype, a recepto r that is expressed at high levels by Purkinje cells and linked to act ivation of protein kinase C (PKC). Down-regulation or blockade of PKC abolished the response to NGF-ACPD. Consistent with the opposite roles of p75 in effects of the two neurotrophins, blockade of mGluR1 or PKC potentiated the survival response elicited by NT-3. In sum, our data suggest that afferent excitatory transmitters activate specific metabo tropic receptors to elicit a p75-mediated action of NGF. NT-3 acts on Purkinje cells by a different mechanism that is not absolutely p75-dep endent and that is reduced by neurotrophin access to p75 and metabotro pic receptor activity.