The neurotrophin receptor p75 ^NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus

Abstract

Neurotrophins are involved in the modulation of synaptic transmission, including the induction of long-term potentiation (LTP) through the receptor TrkB. Because previous studies have revealed a bidirectional mode of neurotrophin action by virtue of signaling through either the neurotrophin receptor p75 NTR or the Trk receptors, we tested the hypothesis that p75 NTR is important for longterm depression (LTD) to occur. Although LTP was found to be unaffected in hippocampal slices of two different strains of mice carrying mutations of the p75 NTR gene, hippocampal LTD was impaired in both p75 NTR -deficient mouse strains. Furthermore, the expression levels of two (RS)-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits, GluR2 and GluR3, but not GluR1 or GluR4, were found to be significantly altered in the hippocampus of p75 NTR -deficient mice. These results implicate p75 NTR in activity-dependent synaptic plasticity and extend the concept of functional antagonism of the neurotrophin signaling system.neurotrophins ͉ p75 neurotrophin receptor ͉ synaptic plasticity N eurotrophins form a small family of dimeric, secretory proteins that exert a broad spectrum of functions on vertebrate neurons. In particular, they are well known for regulating cell fate and cell shape (1, 2). They transduce their effects by binding to two different classes of receptor proteins, the receptor tyrosine kinases of the Trk family (3) and the neurotrophin receptor p75 NTR (4,5). This dual receptor system allows for the transduction of a wide array of signals after ligand binding, which can even be antagonistic. Although the best known trophic functions of neurotrophins are mediated by one of the three Trk receptors, p75 NTR has been implicated in the death of neurons in a variety of CNS areas, including the retina (6), the developing spinal cord (7), and the septal nucleus (8). More recently, p75 NTR has been linked with inhibition of axonal elongation (9, 10). Conversely, Trk receptors are essential for neurotrophin-promoted neurite growth (3).Beyond the regulation of cell fate and shape, neurotrophins and their receptors have emerged as major modulators of synaptic transmission and plasticity. Neurotrophins are secreted by neurons in an activity-dependent fashion (11-13), and numerous studies have indicated a crucial role for BDNF and its receptor TrkB in hippocampal long-term potentiation (LTP). Lack of BDNF, due to either gene or protein inactivation, leads to a profound inhibition of LTP (14-17), whereas addition of BDNF to hippocampal slices isolated from WT animals results in a long-lasting enhancement of synaptic transmission (18). This effect of BDNF on LTP is thought to be mediated by TrkB because this receptor is required for the establishment of LTP (19,20).Much less is known about the role of p75 NTR in synaptic plasticity. Blocking p75 NTR with antibodies does not interfere with the induction of LTP in adult mice (20). However, deletion of p75 NTR has been shown to improve spatial learning (21). Furth...

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

“…In line with this are the results of Lee et al (14), which indicate that NgR1, as one of the interacting partners for NogoA, counteracts the FGF2 action on LTP. An alternative view would be that NogoA restricts synaptic plasticity via p75 NTR , an NgR1-associated component of the Nogo receptor complex, which has been postulated as a mediator of negative synaptic plasticity (42)(43)(44). Because we do not see an effect on LTD after NogoA neutralization, however, it is unlikely that NogoA acts solely via p75 NTR .…”

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Then, CNTF action is specified by the expression of its cognate Trk receptor (CNTFRα) in NE neurons of the brainstem (Ip et al , 1993). It is noteworthy that Trk receptor activation assures fast onset (within 1–2 min) with signaling up to hours depending on the signal transduction pathway (Sermasi et al , 2000; Mizoguchi et al , 2002; Rosch et al , 2005). Thereby, Trk receptors might be best suited to produce activity patterns that match the species' needs for survival and produce evolutionary advantage.…”

The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons

“…In this context, it is interesting that long-term depression (LTD) has been shown to be significantly impaired in p75 NTR KO mice, whereas LTP was shown to be unaffected (Xu et al, 2000;Rösch et al, 2005;Woo et al, 2005). In addition to an increase in spine numbers in p75 NTR KO neurons, there is also a significant difference in spine morphology determining a clear shift in spine type: in p75 NTR KO neurons we found an increased proportion of mushroom (type II) as well as thin (type III) spines.…”

“…For example, BDNF and its receptor TrkB play a crucial role in the induction and maintenance of hippocampal long-term potentiation (LTP) (for review, see Poo, 2001). In contrast, deletion of p75 NTR leads to a significant impairment in long-term depression (Rösch et al, 2005;Woo et al, 2005), without affecting LTP.…”