Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons

Cholinergic neurons innervating cortical structures are among the most affected neuronal populations in Alzheimer's disease. In rodents, they express high levels of the neurotrophin receptor p75(NTR). We have analyzed cholinergic septohippocampal neurons of the medial septal nucleus in p75(exonIII) (partial p75(NTR) knock-out) and p75(exonIV) (complete p75(NTR) knock-out) mice, in their original genetic background and in congenic strains. At postnatal day 15, the p75(exonIII) mutation leads to a moderate increase (+13%) in these neurons among littermates only after back-crossing in a C57BL/6 background. In contrast, the null p75(exonIV) mutation, which prevents expression of both the full-length and the shorter p75(NTR) isoforms, results in a 28% neuronal increase, independent of genetic background. The incomplete nature of the p75(NTR) mutation used previously, coupled with difficulties in delineating the mouse medial septum and the impact of the genetic background on cell numbers, all contribute to explain previous difficulties in establishing the role of p75(NTR) in regulating cholinergic neuron numbers in the mouse forebrain.