Reelin' in clues to memory

Reelin is well known to regulate neuronal migration in embryonic development. More recently, it has been implicated in long-term potentiation in the adult hippocampus. New work, reported in The Journal of Neuroscience, shows that this dual role for Reelin in development and memory involves a shared signalling pathway that influences memory through its regulation of NMDA (N-methyl-D-aspartate) receptor function.

During embryonic development, Reelin regulates the proper positioning of neurons by triggering a cascade of events, starting with its binding to the very low-density lipoprotein (VLDL) receptor (VLDLR) and apolipoprotein E receptor 2 (APOER2), which, in turn, induces tyrosine phosphorylation of the adaptor protein disabled 1 (DAB1).

NMDA receptors (NMDARs) modulate synapse formation and long-term changes in synaptic strength through their control of Ca²⁺ entry into neurons. Phosphorylation and dephosphorylation of tyrosine residues on NR2 subunits of NMDARs is necessary for NMDAR gating activity. It turns out that DAB1 activates Src family kinases (SFKs), which are crucial for phosphorylation of NMDAR subunits. This suggests the intriguing possibility of a relationship between the Reelin-activated developmental signalling pathway and the regulation of synaptic ion channels.

To test this possibility, Chen and colleagues investigated the effects of Reelin on Ca²⁺ influx through NMDARs in primary cortical neurons of rats and mice. In the presence of Reelin, glutamate stimulation led to a striking increase in Ca²⁺ influx through NMDARs, whereas Reelin or glutamate stimulation alone led to no such increase. Blocking Reelin binding to VLDLR and APOER2 prevented the enhancing effects of glutamate-mediated Ca²⁺ influx. A similar effect was observed in neurons that were deficient in DAB1, and, therefore, unable to respond to Reelin. Pharmacological inhibition of SFKs also abolished the enhancing effects of Reelin on Ca²⁺ influx.

Increases in intracellular Ca²⁺ induce long-term changes in synaptic strength through the activation of CREB (cyclic AMP responsive element (CRE) binding protein), which triggers changes in gene transcription and expression. In the presence of Reelin, glutamate induced phosphorylation of CREB, whereas glutamate or Reelin alone had only minor effects. This indicates that Reelin might, ultimately, influence long-term synaptic plasticity by modulating activity-dependent gene transcription through its influence on intracellular Ca²⁺ concentrations.

This work draws together several lines of evidence to support a modulatory role for Reelin in long-term synaptic plasticity in adulthood through its effects on NMDAR gating. Moreover, results indicate that the same Reelin-activated developmental signalling pathway that supports neuronal migration is central to its role in learning and memory.