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 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 Ca(2+) 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 of d-AP-5, indicating that it is independent of NMDA receptors. In contrast, associative LTD was inhibited by (S)-alpha-methyl-4-carboxyphenyl-glycine, indicating the involvement of metabotropic glutamate receptors. Furthermore, associative LTD is dependent on the activation of voltage-gated Ca(2+) channels by postsynaptic action potentials. Both nifedipine, an L-type Ca(2+) channel antagonist, and omega-conotoxin GVIA, a selective N-type channel blocker, abolished the induction of associative LTD. 8-hydroxy-2-dipropylaminotetralin (OH-DPAT), a 5-HT(1A) receptor agonist, inhibited postsynaptic Ca(2+) influx through N-type Ca(2+) 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 Ca(2+) channels provides a gain control for synaptic depression in hippocampal pyramidal neurons.
Normann
C
C
Institute of Physiology, University of Freiburg, D-79104 Freiburg, Germany.
Peckys
D
D
Schulze
C H
CH
Walden
J
J
Jonas
P
P
Bischofberger
J
J
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D013995:Time
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D005456:Fluorescent Dyes; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D002118:Calcium