. The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7362-7. PubMed.

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  1. Rosch and colleagues in the May 17 issue of PNAS provide intriguing new data implicating p75NTR in activity-dependent synaptic plasticity. The authors use two strains of p75NTR mutants (p75NTRexonIV-/- and p75NTRexonII-/-) to investigate the emerging concept of functional antagonism of the p75NTR neurotrophin system in the development and maintenance of hippocampal-induced LTD, a model of synaptic plasticity. In both mutants, the maintenance but not the induction of LTD was impaired compared to wild-type mice. Hippocampal LTP was not affected in these mutant mice. The authors provide information indicating that the p75NTR-impaired hippocampal LTD is potentially the result of altered expression levels of the AMPA receptor subunits, GluR2 and GluR3. Although NGF and BDNF stimulate or inhibit LTD, respectively, (1,2), the precise neurotrophins used by p75NTR in wild-type animals during the initiation of LTD is still unclear. The authors suggest that the neurotrophins NGF and BDNF, which bind to their high affinity trkA and trkB receptors, respectively, as well as to the p75NTR, are candidate neurotrophins to play a crucial role in LDT. Interestingly, these neurotrophins and their receptors are also involved in degeneration of a select neuronal population in Alzheimer disease (AD), particularly the cholinergic basal forebrain cortical projection neurons (3,5). Therefore, it would be of interest to know whether the concept of p75NTR-associated functional antagonism could be extended to neuronal and synaptic dysfunction in AD. In this regard, we have found a decrease in the trkA signal transducing NGF receptor, an increase in proNGF, the precursor molecule for NGF, while the p75NTR remains stable in the cortex during the early stages of AD (3-6). Since proNGF binds with higher affinity to p75NTR than the cognate trkA receptor, the shift in the expression from trkA to proNGF in light of the stability of the p75NTR suggests that p75NTR may play a more dominant role in neuronal dysfunction during the progression of AD. In addition, we have shown that both BDNF and proBDNF are reduced in the cortex early in the onset of AD (7). It is intriguing to speculate that p75NTR binding to proNGF initiates a cascade of events leading to cholinergic cell death and that the reduction in BDNF alters the binding between trkB and p75NTR, affecting synaptic plasticity. Further studies are needed to determine whether the concept of functional antagonism is applicable to the molecular pathologic processes underlying neuronal degeneration in AD.

    See also:

    Peng et al. (in press) J. Neurochem.

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