Associative long-term depression in the hippocampus is dependent on postsynaptic N-type Ca2+ channels

Long-term depression (LTD) is a form of synaptic plasticity that can be ind uced either by low-frequency stimulation of presynaptic fibers or in an ass ociative manner by asynchronous pairing of presynaptic and postsynaptic act ivity. We investigated the induction mechanisms of associative LTD in CA1 p yramidal neurons of the hippocampus using whole-cell patch-clamp recordings and Ca2+ imaging in acute brain slices. Asynchronous pairing of postsynapt ic action potentials with EPSPs evoked with a delay of 20 msec induced a ro bust, long-lasting depression of the EPSP amplitude to 43%. Unlike LTD indu ced by low-frequency stimulation, associative LTD was resistant to the appl ication of D-AP-5, indicating that it is independent of NMDA receptors. In contrast, associative LTD was inhibited by (S)- alpha -methyl-4- carboxyphe nyl-glycine, indicating the involvement of metabotropic glutamate receptors . Furthermore, associative LTD is dependent on the activation of voltage-ga ted Ca2+ channels by postsynaptic action potentials. Both nifedipine, an L- type Ca2+ channel antagonist, and omega -conotoxin GVIA, a selective N-type channel blocker, abolished the induction of associative LTD. 8-hydroxy-2-d ipropylaminotetralin (OH-DPAT), a 5-HT1A receptor agonist, inhibited postsy naptic Ca2+ influx through N-type Ca2+ channels, without affecting presynap tic transmitter release. OH-DPAT also inhibited the induction of associativ e LTD, suggesting that the involvement of N-type channels makes synaptic pl asticity accessible to modulation by neurotransmitters. Thus, the modulatio n of N-type Ca2+ channels provides a gain control for synaptic depression i n hippocampal pyramidal neurons.