Bi-directional alterations of LTP after acute homocysteine exposure

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

“…Previous reports concerning HCY effects on NMDARs are complex (Christie et al 2009;Lipton et al 1997). Our finding that HCY reduces the peak amplitude of GluN2B currents at low (200 nM) GLY is consistent with previous work showing that, in young GluN2B-enriched cortical neurons, HCY reduces calcium flux during brief applications of NMDA in low but not saturating GLY levels (Lipton et al 1997).…”

“…Therefore, HCY has two separate and unique effects on NMDARs that are likely to work in concert: HCY can resemble both GLY and glutamate. This may provide a basis for understanding why low HCY depresses hippocampal LTP, while higher HCY enhances LTP, characteristics of glutamate and GLY, respectively (Christie et al 2009). …”

“…However, while these and other studies suggest that HCY is a weak agonist at the NMDAR glutamate site (Poddar et al 2009), HCY also shows characteristics that are not typical of glutamate site agonists (Christie et al 2009;Lipton et al 1997). For instance, when HCY concentrations ([HCY]) are raised above 100 M, the effect of HCY on LTP reverses: now HCY significantly enhances NMDAR-dependent LTP, which does not occur when NMDA is applied (Christie et al 2009). Moreover, HCY inhibits peak NMDA-induced calcium flux when glycine (GLY) concentrations ([GLY]) are subsaturating in young cultured neurons (Lipton et al 1997).…”

“…This likely explains why DIV9 neurons, which have high GluN2B: GluN2A ratios, did not show significant amplitude reduction in response to L-cysteine. The reduction of NMDAR desensitization by cysteine that spares GluN2B NMDARs from strong peak depression may explain why all concentrations of cysteine, unlike HCY, enhance LTP in hippocampal slices (Christie et al 2009). …”

“…Acutely applied HCY also mimics NMDA in reducing long-term potentiation (LTP) in hippocampal slices (Christie et al 2009). However, while these and other studies suggest that HCY is a weak agonist at the NMDAR glutamate site (Poddar et al 2009), HCY also shows characteristics that are not typical of glutamate site agonists (Christie et al 2009;Lipton et al 1997). For instance, when HCY concentrations ([HCY]) are raised above 100 M, the effect of HCY on LTP reverses: now HCY significantly enhances NMDAR-dependent LTP, which does not occur when NMDA is applied (Christie et al 2009).…”