The Role of p75NTR in Cholinergic Basal Forebrain Structure and Function

The role of the p75 neurotrophin receptor (p75NTR) in adult cholinergic basal forebrain (cBF) neurons is unclear due to conflicting results from previous studies and to limitations of existing p75NTR-knock-out mouse models. In the present study we used a novel conditional knock-out line (ChAT-cre p75in/in) to assess the role of p75NTR in the cBF by eliminating p75NTR in choline acetyl-transferase-expressing cells. We show that the absence of p75NTR results in a lasting increase in cBF cell number, cell size, and cholinergic innervation to the cortex. Analysis of adult ChAT-cre p75in/in mice revealed that mutant animals show a similar loss of cBF neurons with age to that observed in wild-type animals, indicating that p75NTR 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 p75NTR-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 p75NTR expression in existing knock-out models.