The Role of p75^NTRin Cholinergic Basal Forebrain Structure and Function

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.

The Role of BDNF in the Development of Fear Learning

“…However, structural and functional development of the human brain is a nonlinear process, [23,29,66] giving rise to a developmental mismatch model, suggesting that during adolescence subcortical regions are further ahead in their maturation trajectories compared to prefrontal ones. [67] Consistent with this model, magnetic resonance imaging (MRI) scans of human cortical gray matter for subjects between the ages of 4 and 21 years show that high-order association cortices mature later in development compared to sensorimotor regions, whose function they integrate. [68] In the prefrontal cortex, maximum synaptic density peaks at around 4 years of age, [69] followed by a substantial reduction in gray matter between adolescence and adulthood thought to be due to increased myelination in peripheral regions of the cortex that regulate cognitive processes.…”

“…The prefrontal and subcortical brain regions, which regulate fear learning and expression, undergo pronounced developmental changes from childhood into adulthood. However, structural and functional development of the human brain is a nonlinear process, giving rise to a developmental mismatch model, suggesting that during adolescence subcortical regions are further ahead in their maturation trajectories compared to prefrontal ones . Consistent with this model, magnetic resonance imaging (MRI) scans of human cortical gray matter for subjects between the ages of 4 and 21 years show that high‐order association cortices mature later in development compared to sensorimotor regions, whose function they integrate .…”

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…GABAergic vs cholinergic (Sussel et al, 1999; Zhao et al, 2003), striatal cholinergic interneuron vs. BF cholinergic projection neurons (Chen et al, 2010b). These studies, along with those probing the function of cell surface receptors (Boskovic et al, 2014; Cui et al, 2011; Elshatory and Gan, 2008; Jia et al, 2014; Sanchez-Ortiz et al, 2012) reveal subtle differences in the response of distinct populations of neurons within the BFCNs. These differences raise the likelihood that there is an as yet under-appreciated heterogeneity of BFCNs.…”

Neurotrophin biology at NGF 2016: From fundamental science to clinical applications

“…Using a conditional p75NTR knockout mouse, Dr. Boskovic showed that removing p75NTRs in mature postmitotic cholinergic neurons elevated cholinergic signaling and innervation in the basal forebrain. Removing p75NTRs also improved idiothetic navigation (Boskovic et al, 2014). This improvement was concurrent with structural changes – viral tracing revealed that p75NTRs may play a role in guiding basal forebrain neuron axons to their correct postsynaptic targets.…”