When reading about neural development in a textbook, chances are that we will find a clear division between activity-dependent processes and those that do not require neural activity. Are there developmental mechanisms that bridge this divide? Although this question has profound implications, this issue has not, so far, been a mainstream area of research. But now Takasu et al. have provided a breakthrough in this field by showing that Eph receptors can modulate the function of NMDA (N-methyl-d-aspartate) receptor ion channels.

Eph receptors and their ligands, the ephrins, participate in several developmental phenomena, such as segmentation and axon guidance. Previous observations had shown that EphB2 receptors interact with and cluster NMDA receptors at synaptic sites. Takasu et al. explored the functional meaning of such an interaction and found that EphB2 potentiates the influx of calcium through NMDA channels in cortical neurons, an effect that depended on phosphorylation of the NMDA receptor. Although Eph receptors are themselves kinases, this NMDA receptor phosphorylation involves a member of the Src family of kinases. As this increase in NMDA receptor function was also accompanied by an increase in gene expression, it is possible that this new signalling pathway participates in the long-term structural remodelling of the synapse. Indeed, two additional papers point in this direction by showing that the absence of EphB2 impairs long-term synaptic plasticity.

Henderson et al. found that mice lacking EphB2 showed a reduction in hippocampal long-term potentiation (LTP) in both the CA1 region and the dentate gyrus. Grunwald et al. found a similar reduction in CA1 LTP, particularly during its late phase, and marked impairments of both long-term depression (LTD) and a reversal of LTP known as depotentiation. Moreover, Grunwald et al. showed that spatial memory, which depends on hippocampal function, was defective in EphB2 knockout mice.

Together, these findings give a significant push to the idea that Eph receptors are crucially involved in synaptic plasticity, although some observations still need to be reconciled. For example, NMDA receptor phosphorylation requires expression of the full-length EphB2 receptor. By contrast, the presence of a version of EphB2 that lacks the intracellular domain is enough to rescue the effect of the knockout on synaptic plasticity. But despite such differences, these three papers have begun to reveal one way in which nature and nurture interact to give rise to the nervous system.