Learning and memory: A memorable encounter

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Noradrenaline is involved in memory formation by regulating the phosphorylation of GluR1, a subunit of alpha -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors, which then facilitates the insertion of these receptors at postsynaptic sites.

Emotion is thought to be involved in distinguishing significant experiences from less relevant ones, and in aiding their transformation into long-term memory. Noradrenaline has previously been shown to have a role in the emotional regulation of memory, although the molecular mechanism for this process was unknown. Now, Hu and colleagues show that noradrenaline regulates the phosphorylation of GluR1, a subunit of alpha -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors, which then facilitates the insertion of these receptors at postsynaptic sites.

First, the authors tested the effects of noradrenaline on GluR1 phosphorylation in hippocampal slices. They found that it induced phosphorylation at two sites, Ser845 and Ser831, and that this was dependent on beta -adrenergic receptor ( beta -AR) signalling. Similar results were obtained in hippocampi from mice that had been exposed to adrenaline or fox urine (which is known to induce innate fear).

Increasing the number of AMPA receptors in the postsynaptic membrane is a mechanism that is thought to underlie the expression of long-term potentiation. Therefore, the authors looked at GluR1 trafficking to synapses to determine whether phosphorylation of GluR1 by noradrenaline facilitates this process. Using GluR1 tagged with green fluorescent protein, in combination with electrophysiological methods, they showed that, under a low-frequency electrical stimulus (which is insufficient by itself to facilitate the synaptic delivery of GluR1), noradrenaline induces the synaptic incorporation of GluR1. In neurons transfected with a GluR1DD construct, in which amino-acid mutations mimic the permanent phosphorylation of Ser845 and Ser831, a low-frequency electrical stimulus alone induced synaptic delivery of GluR1. To confirm the role of phosphorylation at these sites, the authors used cells expressing GluR1AA, in which phosphorylation at Ser845 and Ser831 is prevented, and found that the application of noradrenaline under a low-frequency electrical stimulus did not result in the synaptic incorporation of GluR1. These results suggest that phosphorylation at Ser845 and Ser831 is both sufficient and necessary for the synaptic delivery of the GluR1-containing AMPA receptors.

Finally, the authors used a contextual fear-conditioning task — a model in which an animal learns to associate a novel context with an aversive stimulus — to test whether the phosphorylation of GluR1 mediates the memory-enhancing effect of noradrenaline. They found that injecting adrenaline (which leads to increased brain noradrenaline) enhanced the formation of contextual memory in wild-type mice. By contrast, GluR1AA knockin mice did not show improved memory following adrenaline administration. These experiments show that it is the phosphorylation of GluR1 at Ser845 and Ser831 that is necessary for noradrenaline to improve contextual memory.

Together, these results provide a molecular mechanism for the involvement of emotion, through noradrenaline-driven phosphorylation of GluR1, in memory formation. As other factors can also modulate GluR1 phosphorylation, these findings might elucidate how drugs such as cocaine and Prozac affect memory.

Elinor Faulkner

References

Hu, H. et al. Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell 131, 160–173 (2007) | Article | PubMed |