Associative Long-Term Depression in the Hippocampus Is Dependent on Postsynaptic N-Type Ca²⁺ Channels

Abstract

Long-term depression (LTD) is a form of synaptic plasticity that can be induced either by low-frequency stimulation of presynaptic fibers or in an associative manner by asynchronous pairing of presynaptic and postsynaptic activity. We investigated the induction mechanisms of associative LTD in CA1 pyramidal neurons of the hippocampus using whole-cell patch-clamp recordings and Ca²⁺ imaging in acute brain slices. Asynchronous pairing of postsynaptic action potentials with EPSPs evoked with a delay of 20 msec induced a robust, long-lasting depression of the EPSP amplitude to 43%. Unlike LTD induced by low-frequency stimulation, associative LTD was resistant to the application ofd-AP-5, indicating that it is independent of NMDA receptors. In contrast, associative LTD was inhibited by (S)-α-methyl-4-carboxyphenyl-glycine, indicating the involvement of metabotropic glutamate receptors. Furthermore, associative LTD is dependent on the activation of voltage-gated Ca²⁺ channels by postsynaptic action potentials. Both nifedipine, an L-type Ca²⁺ channel antagonist, and ω-conotoxin GVIA, a selective N-type channel blocker, abolished the induction of associative LTD. 8-hydroxy-2-dipropylaminotetralin (OH-DPAT), a 5-HT_1Areceptor agonist, inhibited postsynaptic Ca²⁺ influx through N-type Ca²⁺ channels, without affecting presynaptic transmitter release. OH-DPAT also inhibited the induction of associative LTD, suggesting that the involvement of N-type channels makes synaptic plasticity accessible to modulation by neurotransmitters. Thus, the modulation of N-type Ca²⁺ channels provides a gain control for synaptic depression in hippocampal pyramidal neurons.