The role of p75NTR in cholinergic basal forebrain structure and function

Abstract

The role of the p75 neurotrophin receptor (p75(NTR)) in adult cholinergic basal forebrain (cBF) neurons is unclear due to conflicting results from previous studies and to limitations of existing p75(NTR)-knock-out mouse models. In the present study we used a novel conditional knock-out line (ChAT-cre p75(in/in)) to assess the role of p75(NTR) in the cBF by eliminating p75(NTR) in choline acetyl-transferase-expressing cells. We show that the absence of p75(NTR) results in a lasting increase in cBF cell number, cell size, and cholinergic innervation to the cortex. Analysis of adult ChAT-cre p75(in/in) mice revealed that mutant animals show a similar loss of cBF neurons with age to that observed in wild-type animals, indicating that p75(NTR) does not play a significant role in mediating this age-related decline in cBF neuronal number. However, the increased cholinergic axonal innervation of the cortex, but not the hippocampus, corresponded to alterations in idiothetic but not allothetic navigation. These findings support a role for p75(NTR)-mediated regulation of cholinergic-dependent cognitive function, and suggest that the variability in previous reports of cBF neuron number may stem from limited spatial and temporal control of p75(NTR) expression in existing knock-out models.

Keywords: Morris water maze; cholinergic basal forebrain; hippocampus; knock-out; navigation; p75 neurotrophin receptor.