The Journal of Neurophysiology Vol. 84 No. 3 September 2000, pp. 1279-1288
Copyright ©2000 by the American Physiological Society

Transient Removal of Extracellular Mg²⁺ Elicits Persistent Suppression of LTP at Hippocampal CA1 Synapses Via PKC Activation

 ¹Department of Pharmacology and  ²Department of Neurology, College of Medicine, National Cheng-Kung University, Tainan City, Taiwan 70101

Hsu, Kuei-Sen, Wen-Chia Ho, Chiung-Chun Huang, and Jing-Jane Tsai. Transient Removal of Extracellular Mg²⁺ Elicits Persistent Suppression of LTP at Hippocampal CA1 Synapses Via PKC Activation. J. Neurophysiol. 84: 1279-1288, 2000. Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg²⁺-free artificial cerebrospinal fluid (ACSF) exhibited 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 acid (D-APV) and L-type voltage-operated Ca²⁺ channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca²⁺/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor-mediated responses did not show a long-term enhancement in response to a 30-min Mg²⁺-free ACSF application. Additionally, in prior Mg²⁺-free ACSF-treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically 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.