Dissociation of p75 receptors and nerve growth factor neurotrophic effects: lack of p75 immunoreactivity in striatum following physical trauma, excitotoxicity and NGF administration
Affiliations: Alkermes Inc. 64 Sidney Street, Cambridge, MA 02149, USA | Rush-Presbyterian, St. Luke's Medical Center, Tech. 2000, 2242 W. Harrison Street, Chicago, 1L 60612, USA | Tufts University School of Medicine, Department of Pharmacology and Experimental Therapeutics, 136 Harrison Avenue, Boston, MA 02111, USA
Abstract: While the function and regulation of the low affinity (p75) nerve growth factor (NGF) receptor in the central nervous system (CNS) remains a mystery, one of the more intriguing observations involves its response to injury in the adult rat striatum. Following mechanical injury to the striatum, a re-expression of striatal p75 receptors and mRNA purportedly occurs (apparently mediated by elevations in NGF), thus reversing the natural loss of these phenotypic markers that is known to occur during development. This observation has important implications for understanding both the regulation of NGF neurotrophic activity and the role of the p75 receptor, for it implies that the presence of this receptor may be required for NGF trophic activity in the CNS. In an effort to gain a greater understanding of the function and regulation of the low affinity p75 NGF receptor, we performed a series of experiments to study the injury-induced, re-expression phenomenon in the striatum. In the first experiment, we duplicated the mechanical, cannula-induced injury used in the original study. In a follow-up study, we exacerbated that injury by infusing quinolinic acid directly into the striatum. In a third study, the mechanical injury was complemented with chronic striatal infusions of NGF. In a final study, we examined striatal tissue from rats who had been protected from striatal quinolinic acid neurotoxicity by administration of NGF. In no instance was the re-expression of p75 striatal receptors observed, despite positive controls for (a) effective neural trauma, confirmed by histologic and immunocytochemical methods, (b) effective antibody staining, confirmed by appropriate basal forebrain p75 immunoreactivity, and (c) effective biological activity of exogenous NGF, confirmed by hypertrophy of choline acetyltransferase (ChAT)-positive striatal neurons and protection of ChAT-positive striatal neurons against excitotoxicity. At least two important conclusions can be drawn from these studies: (1) the presence or induction of low affinity p75 receptors is not necessary, while the presence of constitutive high affinity tropomyosin related kinase (trk) NGF receptors seem sufficient for NGF trophic activity in the CNS, and (2) the variables necessary to induce re-expression of p75 striatal receptors in adult rats have not yet been elucidated and are apparently complex.
