Abstract
p75 is expressed among Purkinje cells in the adult cerebellum, but its function has remained obscure. Here we report that p75 is involved in maintaining the frequency and regularity of spontaneous firing of Purkinje cells. The overall spontaneous firing activity of Purkinje cells was increased in p75(-/-) mice during the phasic firing period due to a longer firing period and accompanying reduction in silence period than in the wild type. We attribute these effects to a reduction in small conductance Ca(2+)-activated potassium (SK) channel activity in Purkinje cells from p75(-/-) mice compared with the wild type littermates. The mechanism by which p75 regulates SK channel activity appears to involve its ability to activate Rac1. In organotypic cultures of cerebellar slices, brain-derived neurotrophic factor increased RacGTP levels by activating p75 but not TrkB. These results correlate with a reduction in RacGTP levels in synaptosome fractions from the p75(-/-) cerebellum, but not in that from the cortex of the same animals, compared with wild type littermates. More importantly, we demonstrate that Rac1 modulates SK channel activity and firing patterns of Purkinje cells. Along with the finding that spine density was reduced in p75(-/-) cerebellum, these data suggest that p75 plays a role in maintaining normalcy of Purkinje cell firing in the cerebellum in part by activating Rac1 in synaptic compartments and modulating SK channels.
Highlights
The role of p75 in Purkinje cells of the adult cerebellum has remained obscure
We attribute this to the ability of p75 to activate Rac1, because RacGTP levels are reduced in the p75Ϫ/Ϫ cerebellum, and inhibiting Rac1 attenuated small conductance Ca2ϩ-activated Kϩ (SK)-mediated tail currents to a similar extent as in p75Ϫ/Ϫ Purkinje cells in cerebellar slices (28% by NSC23766 and 21% in p75Ϫ/Ϫ mice)
We demonstrated that BDNF activated Rac1 primarily through p75 in organotypic cerebellar slices; BDNF did not increase RacGTP levels in p75Ϫ/Ϫ mice, and inhibiting TrkB with K252a had no effect on Rac1 activation by BDNF
Summary
The role of p75 in Purkinje cells of the adult cerebellum has remained obscure. Results: In the absence of p75, RacGTP levels from the cerebellum were reduced, and the mean firing frequency for all phasic firing Purkinje cells was increased. The role of p75 in septal cholinergic neurons appears to be related to cell survival and degeneration [1], its role in Purkinje cells has remained largely undetermined It has been reported, based on analysis of compound BDNFϩ/Ϫ:p75Ϫ/Ϫ mice, that p75 plays a role in dendritic development of Purkinje cells and cerebellar fissure formation, both in BDNF3-dependent and -independent manners [2]. As one of the small GTPases, Rac plays a central role in spine formation during development and in the adult, thereby regulating synaptic activity in a wide variety of neurons [5]. We report that p75 activates Rac in synaptic compartments of cerebellar Purkinje cells, and this activation plays a role in maintaining normal firing regularity of Purkinje neurons through, at least in part, regulation of small conductance Ca2ϩ-activated Kϩ (SK) channels
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