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1 August 2005. In life, you wouldn’t trust a child to do an adult’s job. In the brain, the same might be true. While the mature form of brain-derived neurotrophic factor (BDNF) may stimulate long-term potentiation (LTP), or the strengthening of synaptic connections that is required for learning and memory, the immature, proBDNF not only fails in this regard, it does exactly the opposite, stimulating long-term depression (LTD). So concludes an article in last week’s Nature Neuroscience online.
Bai Lu, Cornell University, New York, and colleagues there and at the National Institute of Child Health and Human Development, Bethesda, Maryland, realized the rebellious nature of the immature neurotrophic factor when studying the effect of the neurotrophin receptor, p75NTR. This cell surface receptor binds to a variety of ligands and is known to promote apoptosis, or programmed cell death. However, ablating the gene for p75NTR in mice does little to prevent neuronal cell death, and in fact leads to sensory deficits, suggesting the receptor has other roles besides triggering apoptosis (see Lee et al., 1992).
To pinpoint what else p75NTR might get up to in the brain, first author Newton Woo and colleagues characterized the electrophysiological properties of hippocampal slices from p75NTR-negative mice. Woo found that while basic neurotransmission was normal in CA1 neurons, LTD elicited by transmission through the N-methyl-D-aspartate glutamate receptor was significantly compromised. In p75NTR-/- neurons, low frequency stimulation did stimulate LTD at first, but within 60 minutes transmission was fully back to normal, whereas LTD persists in p75NTR+/+ neurons for many hours.
The high-affinity ligand for p75, proBDNF, came in for scrutiny next. When Woo preincubated hippocampal slices with the rookie neurotrophin, then stimulated LTD, he found there was a small (about 17 percent) yet significant enhancement of the depression. However, in p75NTR-/- hippocampal slices, proBDNF had no effect on LTD, confirming the involvement of the neurotrophin receptor. ProBDNF also had no effect in the presence of ifenprodil, an inhibitor of the NR2B subunit of the NMDA receptor, suggesting that the proBDNF/p75NTR interaction acts through this subunit, which is known to be involved in LTD. In fact, using immunohistochemistry measurements, Woo and colleagues found that p75NTR is colocalized in the hippocampus with postsynaptic density 95 (PSD95), a protein normally found in synapses. This localization puts the neurotrophin receptor in close proximity to NR2B. Furthermore, when the authors treated hippocampal slices with proBDNF, they observed about a 50 percent increase in NMDA currents, but only in p75NTR+/+ animals.
“These results provide strong support for the idea that endogenously secreted proBDNF, by acting on p75NTR, promotes NMDA-dependent LTD by enhancing the expression of NR2B at CA1 synapses,” write the authors. The results also support the growing realization that immature neurotrophins try to resist the actions of their mature counterparts. Thus, while BDNF and proBDNF stimulate LTP and LTD, respectively, neurotrophic growth factor (NGF) and proNGF protect or stimulate neuronal apoptosis, respectively, through their actions on p75NTR and tyrosine receptor kinase A (TrkA).
Of course, various neurotrophic factors have been tested in laboratory animals and in clinical trials for their abilities to protect against neurodegeneration. While a phase I clinical trial of glial-derived neurotrophic factor in patients with Parkinson disease has recently been halted (see Alzheimer Research Forum related news story), a small trial of NGF in AD patients has produced some promising results (see Alzheimer Research Forum related news story). As for BDNF, numerous studies have shown that levels of both forms of the protein are lowered in various parts of the AD brain (see Alzheimer Research Forum related news story). Now, these latest findings suggest that the ratio of pro- and mature BDNF might be a key factor in regulating the balance between LTP and LTD. For this reason, understanding what prompts the rookie proBDNF to mature may be crucial.—Tom Fagan.
Woo NH, Teng HK, Siao C-J, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 2005 Aug;8(8):1069-77. Epub 2005 Jul 17. Abstract