p75(NGFR) and cholinergic neurons in the developing forebrain: a re-examination.

The low-affinity nerve growth factor receptor (p75(NGFR)) apparently can mediate apoptosis in a variety of cells in vitro and in vivo. Previously, our laboratory suggested that p75(NGFR) induced apoptosis in a subpopulation of cholinergic forebrain neurons during postnatal development, i.e., the number of choline acetyltransferase (ChAT)-positive neurons in a control strain of mice decreased whereas it remained higher in p75(NGFR)-deficient (-/-) mice. Discrepancies with subsequent data sets in our laboratory caused us to thoroughly re-analyze the fate of these cholinergic medial septum and neostriatal neurons in new sets of p75(NGFR) -/- and two DNA control strains of mice during development. Between postnatal day (P)6 and P15 the number of ChAT-positive neurons detected in the medial septum of 129/Sv mice and Balb/c mice increased by approximately 64% and approximately 62%, respectively. This increase is contrary to previous reports from our laboratory and indicative of normal postnatal development (including an increase in ChAT-enzyme) of the cholinergic forebrain neurons. In p75(NGFR) -/- mice the number of ChAT-positive neurons in the medial septum remained constant between P6 and P15 and was approximately 31% and approximately 56% higher at P6 than 129/Sv and Balb/c mice, respectively. At P15 and adulthood, p75(NGFR) -/- mice had similar numbers of cholinergic neurons as control mice. In the developing neostriatum, the number of ChAT-positive neurons increased by approximately 56% between P6 and P15 and did not differ between p75(NGFR) -/- and control mice at any time. Analyses for apoptotic DNA fragmentation (TUNEL labeling) at P8 revealed no differences between p75(NGFR) -/- and control mice in 12 forebrain regions, including the septum and neostriatum. At all times, all mice had similar levels of acetylcholinesterase-positive cholinergic innervation of the molecular layer in the dorsal dentate gyrus. These findings suggest that the p75(NGFR) does not necessarily mediate apoptosis in medial septum or neostriatal cholinergic neurons during the postnatal time period. The discrepant results of the previous study are most likely due to a less rigorous application of criteria for data acquisition, including anatomical boundaries that define the nucleus.