The cellular mechanisms of long-term potentiation (LTP) have been widely studied because of the attractive idea that LTP may underlie learning and memory. In many parts of the brain, LTP depends on the NMDA receptor class of ionotropic glutamate receptors. Two independent groups show in this issue that NMDA receptors are negatively regulated by small-conductance, calcium-activated potassium channels (SK channels), and that this modulation can affect LTP.

NMDA receptors are normally subject to a voltage-dependent magnesium block, and so make a limited contribution to basal synaptic transmission. However, when the cell is depolarized, these receptors become active, allowing calcium to enter. Activation of NMDA receptors—and the resulting calcium influx—are required for LTP in many brain areas, including the hippocampus and lateral amygdala. The new papers show, however, that this calcium influx activates a negative feedback loop through SK channels that depresses the synaptic potential and turns off the NMDA-receptor response.

John Adelman and colleagues report on page 642 that in hippocampal pyramidal neurons (labeled with green fluorescent protein in the photo), NMDA receptors are colocalized with SK channels (labeled in red) at spines. Using two-photon laser scanning microscopy and two-photon uncaging of glutamate, the authors show that within individual spines, SK channels act to reduce the magnitude of a calcium transient evoked by NMDA receptor activation. During an excitatory postsynaptic potential (EPSP), calcium opens SK channels, which then provide a local shunting current to reduce the EPSP and promote a magnesium-dependent block of NMDA receptors. Blocking SK channels (with apamin, a component of bee venom) enhances NMDA receptor–dependent calcium signals and facilitates induction of long-term potentiation.

This intricate relationship between SK channels and NMDA receptors is not restricted to hippocampal neurons. In a related article, on page 635, Pankaj Sah and colleagues show that a similar mechanism operates in synapses in the lateral amygdala. In pyramidal neurons of the lateral amygdala, Sah and colleagues find that calcium influx via activated NMDA receptors also activates postsynaptic SK channels, and that activation of these SK channels depresses the synaptic potential. They also demonstrate that blockade of SK channels increases LTP of cortical inputs to lateral amygdala pyramidal neurons.