The p75 neurotrophin receptor has nonapoptotic antineurotrophic actions in the basal forebrain

Because of controversy about the role of the p75 neurotrophin receptor (p75(NTR) ) in the cholinergic basal forebrain (CBF), we investigated this region in p75(NTR) third exon knockout mice that were congenic with 129/Sv controls. They express a shortened intracellular form of p75(NTR) , permitting detection of p75(NTR) -expressing cells. We performed separate counts of choline acetyltransferase (ChAT)-expressing and p75(NTR) -expressing neurons. In agreement with past reports, the number of ChAT-immunoreactive neurons in knockout mice was greater than in wild-type mice, and this was evident in each of the main anatomical divisions of the CBF. In contrast, the number of p75(NTR) -immunoreactive neurons did not differ between genotypes. The biggest increase in ChAT neurons (27%) was in the horizontal limb of the diagonal band of Broca (HDB), in which region the number of p75(NTR) -positive neurons was unchanged. Double staining revealed that some neurons in wild-type mice expressed p75(NTR) but not ChAT. In the knockout mice, all p75(NTR) -expressing neurons expressed ChAT. The increase in cholinergic neurons, therefore, was at least partially attributable to a higher proportion of ChAT immunoreactivity within the population of p75(NTR) -expressing neurons. Cholinergic neurons were also larger in knockout mice than in controls. In the hippocampal CA1 region, knockout mice had a greater number of cholinergic fibers. There was a 77% increase in hippocampal ChAT activity in knockout mice and a 38% increase in heterozygotes. The data do not support an apoptotic role but indicate a broad antineurotrophic role of p75(NTR) in the cholinergic basal forebrain.