Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice

Abstract

The p75 low affinity neurotrophin receptor (p75) can induce apoptosis in various neuronal and glial cell types. Because p75 is expressed in the cholinergic neurons of the basal forebrain, p75 knockout mice may be expected to show an increased number of neurons in this region. Previous studies, however, have produced conflicting results, suggesting that genetic background and choice of control mice are critical. To try to clarify the conflicting results from previous reports, we undertook a further study of the basal forebrain in p75 knockout mice, paying particular attention to the use of genetically valid controls. The genetic backgrounds of p75 knockout and control mice used in this study were identical at 95% of loci. There was a small decrease in the number of cholinergic basal forebrain neurons in p75 knockout mice at four months of age compared with controls. This difference was no longer apparent at 15 months due to a reduction in numbers in control mice between the ages of 4 and 15 months. Cholinergic cell size in the basal forebrain was markedly increased in p75 knockout mice compared with controls. Spatial learning performance was consistently better in p75 knockout mice than in controls, and did not show any deterioration with age. The results indicate that p75 exerts a negative influence on the size of cholinergic forebrain neurons, but little effect on neuronal numbers. The markedly better spatial learning suggests that the function, as well as the size, of cholinergic neurons is negatively modulated by p75.

β-Amyloid1–42Induces Neuronal Death through the p75 Neurotrophin Receptor

“…Although our analysis did not specifically determine that ChAT-positive cells had died after A␤ 1-42 exposure at axonal terminals, it did demonstrate the loss of cellular neurotransmitter production and hence loss of function of these neurons. It has also been shown in aged animals that ChAT downregulation correlates with loss of hippocampal function (Yeo et al, 1997) and that this precedes the death of basal forebrain neurons (Greferath et al, 2000).…”

“…To determine cell survival of cholinergic basal forebrain neurons, the rostral half of each brain between Ϫ1.4 and Ϫ0.5 mm from bregma (the medial septum and diagonal band of Broca) was cut by vibratome into 15 60-m-thick serial coronal sections. Floating sections were stained with a rabbit anti-choline acetyltransferase (ChAT) polyclonal antibody (1:500; Ab143; Millipore Bioscience Research Reagents), and all ChAT-positive neurons in the area of interest were counted based on the method of Greferath et al (2000).…”

BDNF Exerts Contrasting Effects on Peripheral Myelination of NGF-Dependent and BDNF-Dependent DRG Neurons

“…p75NTRϪ/Ϫ mice were obtained from a colony previously shown to be 95% congenic to the inbred SVJ-129 strain (Greferath et al, 2000) and subsequently back-crossed a further 12 generations.…”

Disruption of Foxg1 expression by knock-in of Cre recombinase: Effects on the development of the mouse telencephalon

“…Genetic background has long been known to influence the behavioral phenotype of mutant mice (Shanks and Anisman, 1988,Gerlai, 1996,Logue et al, 1997,Bouwknecht and Paylor, 2002,Schauwecker, 2002,McKhann et al, 2003,Sik et al, 2003,Waddell et al, 2004, but fewer studies have focused on the brain-based mechanisms for such strain dependence. Brain (Bilovocky et al, 2003) and limb (Murcia et al, 2004) phenotypes caused by mutation of the Engrailed-1 (en-1) gene are highly dependent upon genetic background, as are the neural phenotypes produced by mutations of p75NGF (Greferath et al, 2000), Unc5c (Burgess et al, 2006), fmr-1 (Paradee et al, 1999,Dobkin et al, 2000,Ivanco and Greenough, 2002,Mineur et al, 2002,Errijgers and Kooy, 2004 and Pax2 (Schwarz et al, 1997). Herrup and colleagues have identified one significant modifier and several other possible loci that may be responsible for trait differences in limb and cerebellum specification in the en-1 knockout (Murcia et al, 2004,Murcia et al, 2006, and a recent report identified a major modifier locus that influences phrenic motor axon guidance in the absence of Unc5c (Burgess et al, 2006).…”