We have used rapid confocal microscopy to investigate the mechanism of Ca(2+) signals in individual dendritic spines of hippocampal CA1 pyramidal cells. The experiments focused on the signals that occur during single weak synaptic responses that were subthreshold for triggering postsynaptic action potentials. These Ca(2+) signals were not strongly affected by blocking the EPSPs with the AMPA receptor antagonist CNQX. The signals were also not strongly reduced by blocking T-type voltage-gated Ca(2+) channels (VGCCs) with Ni(2+) or by blocking a broad range of VGCCs with intracellular D890. The spine Ca(2+) signals were blocked by NMDA receptor channel (NMDAR) antagonist and had the voltage dependence characteristic of these channels. Neither ryanodine nor cyclopiazonic acid (CPA), substances known to deplete intracellular Ca(2+) stores, substantially reduced the amplitude of synaptically evoked Ca(2+) signals. CPA slowed the recovery phase of Ca(2+) signals in spines produced by synaptic stimulation or by backpropagating action potentials, suggesting a role of intracellular stores in Ca(2+) reuptake. Thus, we find that Ca(2+) release from intracellular stores is not required to produce spine Ca(2+) signals. We conclude that synaptic Ca(2+) signals in spines are primarily caused by Ca(2+) entry through NMDARs. Although these channels are largely blocked by Mg(2+) at voltages near the resting potential, they can nevertheless produce significant Ca(2+) elevation. The resulting Ca(2+) signals are an integral component of individual evoked or spontaneous synaptic events and may be important in the maintenance of synaptic function.

CaMKII is a major synaptic protein that is activated during the induction of long-term potentiation (LTP) by the Ca2+ influx through NMDARs. This activation is required for LTP induction, but the role of the kinase in the maintenance of LTP is less clear. Elucidating the mechanisms of maintenance may provide insights into the molecular processes that underlie the stability of stored memories. In this brief review, we will outline the criteria for evaluating an LTP maintenance mechanism. The specific hypothesis evaluated is that LTP is maintained by the complex of activated CaMKII with the NMDAR. The evidence in support of this hypothesis is substantial, but further experiments are required, notably to determine the time course and persistence of complex after LTP induction. Additional work is also required to elucidate how the CaMKII/NMDAR complex produces the structural growth of the synapse that underlies late LTP. It has been proposed by Frey and Morris that late LTP involves the setting of a molecular tag during LTP induction, which subsequently allows the activated synapse to capture the proteins responsible for late LTP. However, the molecular processes by which this leads to the structural growth that underlies late LTP are completely unclear. Based on known binding reactions, we suggest the first molecularly specific version of tag/capture hypothesis: that the CaMKII/NMDAR complex, once formed, serves as a tag, which then leads to a binding cascade involving densin, delta-catenin, and N-cadherin (some of which are newly synthesized). Delta-catenin binds AMPA-binding protein (ABP), leading to the LTP-induced increase in AMPA channel content. The addition of postsynaptic N-cadherin, and the complementary increase on the presynaptic side, leads to a trans-synaptically coordinated increase in synapse size (and more release sites). It is suggested that synaptic strength is stored stably through the combined actions of the CaMKII/NMDAR complex and N-cadherin dimers. These N-cadherin pairs have redundant storage that could provide informational stability in a manner analogous to the base-pairing in DNA.

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Intracellular recordings were used to measure the action spectrum of light adaptation in barnacle photoreceptors. The action spectrum closely resembles the absorption spectrum of rhodopsin (lambdamax at 530 nanometers) and is clearly different from that of metarhodopsin (lambdamax at 495 nanometers). These results suggest that absorption of light by rhodopsin initiates both excitation and light adaptation. The previously reported antagonistic process initiated by metarhodopsin does not appear to play a role at moderate light intensities.