Transient removal of extracellular Mg2+ elicits persistent suppression of LTP at hippocampal CA1 synapses via PKC activation

Previous work has shown that seizure-like activity can disrupt the inductio n of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecula r mechanisms underlying this process better, a set of studies was implement ed in area CA1 of rat hippocampal slices using extracellular recording meth ods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg2+-free artificial cerebrospinal fluid (ACSF) exhib ited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N -methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphovaleric a cid (D-APV) and L-type voltage-operated Ca2+ channel (VOCC) blocker nimodip ine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline- 2, 3-dione (CNQX). In addition, this suppressive effect was specifically block ed by the selective protein kinase C (PKC) inhibitor NPC-15437. However, ne ither Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP- dependent protein kinase inhibitor Rp-adenosine 3',5'-cyclic monophosphothi oate (Rp-cAMPS) affected this suppressive effect. This persistent suppressi on of LTP was not secondary to the long-lasting changes in NMDA receptor ac tivation, because the isolated NMDA receptor-mediated responses did not sho w a long-term enhancement in response to a 30-min Mg2+-free ACSF applicatio n. Additionally, in prior Mg2+-free ACSF-treated slices, the entire frequen cy-response curve of LTP and long-term depression (LTD) is shifted systemat ically to favor LTD. These results suggest that the increase of Ca2+ influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.