A Calcium-Dependent Mechanism of Neuronal Memory

A neuron's record of its previous activity underlies animal memory. A new study reveals a role for the release of calcium ions from intracellular stores in mediating spatially compartmentalized memory of the activity history of a neuron.

can "remember" its previous history of activity and express this memory as a sustained increase in the amplitude of Ca 2+ transients in a spine-specific manner (Fig 1).
The authors performed their experiments in neurons from different regions of the rat brain implicated in memory storage. The contribution of ryanodine receptors to the Ca 2+ transient enhancement was evaluated using different pharmacological approaches-drugs that emptied the Ca 2+ stores or blocked the ryanodine receptors also eliminated the enhancement, but only marginally affected the transients themselves, which were mostly mediated by voltage-gated Ca 2+ channels.
Intriguingly, by measuring Ca 2+ concentration variations on several spines simultaneously, the authors discovered that enhancement of Ca 2+ transients was compartmentalized; it happened in a spine-restricted manner, without diffusing from one spine into another.
Because the spines are specialized in receiving incoming information from other neurons, it was a natural question for the authors to ask whether synaptic activity could be contributing to the enhancement of Ca 2+ transients. Surprisingly, a cocktail of pharmacological agents that blocked the main types of excitatory and inhibitory transmission in the brain did not block the sustained increase in Ca 2+ transients induced by back-propagating action potentials. The cytoplasmic Ca 2+ elevation induced by the activation of the ryanodine receptors is therefore the most likely biochemical link between the activity-dependent membrane depolarization (i.e., the initial back-propagating action potentials) and the downstream signaling events that result in Ca 2+ transient enhancement. This idea was supported by the fact that if a Ca 2+ buffer was used to blunt the cytosolic Ca 2+ increase during the train of back-propagating action potentials then the enhancement was eliminated.
The authors discovered that, surprisingly, emptying the intracellular Ca 2+ stores after the burst of back-propagating action potentials did not affect potentiation. This result indicates that release of Ca 2+ from the stores via ryanodine receptors is important for the initial establishment, but not for the subsequent expression, of the enhancement of Ca 2+ transients.
Because it is impossible to experimentally measure the temporal and spatial distribution of Ca 2+ ions in the tiny volume of the dendritic spines, the author used mathematical modeling to determine that the Ca 2+ released via the ryanodine receptors acted on a (still unknown) target in a specific nanodomain close to the intracellular stores during the initial establishment of the Ca 2+ transient enhancement induced by back-propagating action potentials.
Many questions remain open. For example, it is not clear why the back-propagating action potentials induce Ca 2+ transient potentiation enhancement in only about half of the spines studied. In addition, the physiological stimuli that induce this effect-and the consequences of the sustained Ca 2+ increases on the morphology and function of the dendritic spines-were not investigated. In the end, exactly how this potentiation modulates the way in which neurons communicate with each other is still unknown. This research by Johenning and colleagues is an important step forward, since it uncovers a new spine-restricted mechanism of storing the patterns of previous neuronal activity and defines the role of intracellular Ca 2+ stores and ryanodine receptors in this form of cellular memory.