The role of p75NTR in cholinergic basal forebrain structure and function - PubMed (original) (raw)

The role of p75NTR in cholinergic basal forebrain structure and function

Zoran Boskovic et al. J Neurosci. 2014.

Abstract

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

Keywords: Morris water maze; cholinergic basal forebrain; hippocampus; knock-out; navigation; p75 neurotrophin receptor.

Copyright © 2014 the authors 0270-6474/14/3413033-06$15.00/0.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

The Ngfr mutant gene (p75fl/fl) and inversion strategy used to generate p75in/in mutants. In cells expressing cre recombinase, the loxP-flanked region inverts to generate p75in/in mutants that express mCherry rather than p75NTR from the endogenous Ngfr promoter. UTR, Untranslated region.

Figure 2.

Figure 2.

Loss of p75NTR expression in p75in/in mutants. A, In situ hybridization for p75NTR intracellular domain (p75ICD) mRNA in coronal sections of the medial septum/diagonal band of Broca (MS/DBB) of mutant animals. p75fl/fl and p75exonIII animals contain many p75ICD mRNA-expressing cells, whereas expression of p75NTR mRNA in ChAT-cre p75in/in mice is almost completely absent. B, Immunostaining of the MS/DBB in coronal sections from ChAT-cre p75in/in animals. Expression of the extracellular (p75ECD) or intracellular (p75ICD) domain of p75NTR is not found in ChAT- or Cherry-positive neurons; n = 3 animals per group. Scale bars: A, 20 μm; B, 100 μm.

Figure 3.

Figure 3.

Absence of p75NTR from the adult cBF induces a lasting increase in cell numbers and cell surface area and an increase in cholinergic innervation to layer V somatosensory cortex. Quantification of ChAT-positive cell number (A) and surface area (B) of cBF neurons in ChAT-cre p75in/in mice at 1 and 8 months of age (n = 3 animals per group, 90 cells per genotype). ChAT-immunostained coronal sections of the cortex (C, D, and expanded in E) of p75fl/fl (C) and ChAT-cre p75in/in (D) animals. F, Quantification of the intensity of immunostaining of ChAT-positive fibers reveals a significant increase in the intensity of ChAT in layer V of the cortex; n = 3 animals, 15 sections per group. Scale bars: C, D, 100 μm; E, 20 μm.

Figure 4.

Figure 4.

Mutant animals show an improvement in idiothetic navigation. A, Idiothetic navigation was tested using a modified version of the active place avoidance in an uncued nonrotating arena. On the test day, mutant animals received significantly fewer shocks compared with control animals (B; p = 0.0323), showed a tendency for fewer entries into the shock zone (C; p = 0.0738), and spent longer periods avoiding the shock zone (D; p = 0.0665); n = 11 animals per group. n.s., Not significant.

References

    1. Barrett GL, Reid CA, Tsafoulis C, Zhu W, Williams DA, Paolini AG, Trieu J, Murphy M. Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice. Hippocampus. 2010;20:145–152. doi: 10.1002/hipo.20598. -DOI -PubMed
    1. Baxter MG, Chiba AA. Cognitive functions of the basal forebrain. Curr Opin Neurobiol. 1999;9:178–183. doi: 10.1016/S0959-4388(99)80024-5. -DOI -PubMed
    1. Bernabeu RO, Longo FM. The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis. BMC Neurosci. 2010;11:136. doi: 10.1186/1471-2202-11-136. -DOI -PMC -PubMed
    1. Catts VS, Al-Menhali N, Burne TH, Colditz MJ, Coulson EJ. The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours. Eur J Neurosci. 2008;28:883–892. doi: 10.1111/j.1460-9568.2008.06390.x. -DOI -PubMed
    1. Chambers D, Wilson LJ, Alfonsi F, Hunter E, Saxena U, Blanc E, Lumsden A. Rhombomere-specific analysis reveals the repertoire of genetic cues expressed across the developing hindbrain. Neural Dev. 2009;4:6. doi: 10.1186/1749-8104-4-6. -DOI -PMC -PubMed

MeSH terms

Substances

LinkOut - more resources