Coincidence detection and stress modulation of spike time-dependent long-term depression in the hippocampus.
Associative long-term depression (LTD) in the hippocampus is a form of spike time-dependent synaptic plasticity that is induced by the asynchronous pairing of postsynaptic action potentials and EPSPs. Although metabotropic glutamate receptors (mGluRs) and postsynaptic Ca(2+) signaling have been suggested to mediate associative LTD, mechanisms are unclear further downstream. Here we show that either mGluR1 or mGluR5 activation is necessary for LTD induction, which is therefore mediated by group I mGluRs. Inhibition of postsynaptic phospholipase C, inositol-1,4,5-trisphosphate, and PKC prevents associative LTD. Activation of PKC by a phorbol ester causes a presynaptic potentiation of synaptic responses and facilitates LTD induction by a postsynaptic mechanism. Lithium, an inhibitor of the PKC pathway, inhibits LTD and the presynaptic and postsynaptic effects of the phorbol ester. Furthermore, LTD is sensitive to the postsynaptic application of synthetic peptides that inhibit the interaction of AMPA receptors with PDZ domains, suggesting an involvement of protein interacting with C-kinase 1 (PICK1)-mediated receptor endocytosis. Finally, enhanced PKC phosphorylation, induced by behavioral stress, is associated with enhanced LTD. Both increased PKC phosphorylation and stress-induced LTD facilitation can be reversed by lithium, indicating that this clinically used mood stabilizer may act on synaptic depression via PKC modulation. These data suggest that PKC mediates the expression of associative LTD via the PICK1-dependent internalization of AMPA receptors. Moreover, modulation of the PKC activity adjusts the set point for LTD induction in a behavior-dependent manner.
Niehusmann
Pitt
P
Department of Psychiatry, University of Freiburg, D-79104 Freiburg, Germany.
Seifert
Gabriel
G
Clark
Kristin
K
Atas
Hasan C
HC
Herpfer
Inga
I
Fiebich
Bernd
B
Bischofberger
Josef
J
Normann
Claus
C
D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors; D018020:Lithium Compounds / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D054731:PDZ Domains / Q000187:drug effects; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D018020:Lithium Compounds; D010703:Phorbol Esters; D018094:Receptors, Metabotropic Glutamate; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases
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