ABSTRACT
Domoic acid (DOM) is known to cause hippocampal neuronal damage and produces amnesic effects. We examined synaptic plasticity changes induced by DOM exposure in rat hippocampal CA1 region. Brief bath application of DOM to hippocampal slices produces a chemical form of long-term potentiation (LTP) of CA1 field synaptic potentials. The potentiation cannot be blocked by NMDA receptor antagonist MK-801 but can be blocked by the calcium-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 or cAMP-dependent protein kinase (PKA) inhibitor H-89. DOM-potentiated slices show decreased autophosphorylated CaMKII (p-Thr286), an effect that is also dependent on the activity of CaMKII and PKA. Increased phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluR1 (p-Ser831) was seen in DOM-potentiated slices. Therefore, aberrant regulation of CaMKII and GluR1 phosphorylation occurs after DOM application. In addition, tetanus-induced LTP as well as the increase of phosphorylation of CaMKII (p-Thr286) were reduced in DOM-potentiated slices. Compared with brief exposure, slices recovering from prolonged exposure did not show potentiation or altered levels of CaMKII (p-Thr286) or GluR (p-Ser831). However, decreased phosphorylation of GluR1 at Ser845 was seen. These results describe a new chemical form of LTP and uncover novel molecular changes induced by DOM. The observed impairment of tetanus LTP and misregulation of CaMKII and GluR1 phosphorylation may partially account for DOM neurotoxicity and underlie the molecular basis for DOM-induced memory deficit.
Subject(s)
Hippocampus/drug effects , Kainic Acid/analogs & derivatives , Long-Term Potentiation/drug effects , Neuromuscular Depolarizing Agents/pharmacology , Tetanus/physiopathology , Animals , Blotting, Western , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Electrophysiology , Enzyme Activation/drug effects , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Kainic Acid/pharmacology , Male , Memory Disorders/chemically induced , Memory Disorders/psychology , Neuronal Plasticity/drug effects , Phosphorylation , Protein Kinases/metabolism , Rats , Rats, Sprague-Dawley , Receptors, AMPA/metabolismABSTRACT
To determine whether metabotropic glutamate receptors (mGluRs) contribute to the responses of neurons to repetitive stimulation in the rat auditory cortex in vitro, five stimulus pulses were delivered at 2-100 Hz which elicited five depolarizing synaptic responses, f-EPSPs: f-EPSPs(1-5). Stimulus pulses 2-5 delivered at low frequencies (2-10 Hz) elicited f-EPSPs(2-5) that were about 15% smaller than the response elicited by the first pulse (f-EPSP(1)). In the presence of the nonspecific mGluR agonist, ACPD, the amplitude of all f-EPSPs was 40% smaller than predrug responses. APV, CNQX, or bicuculline (antagonists of NMDA-, AMPA/kainate-, and GABA(A)-receptors, respectively) did not change this effect of ACPD. The mGluR antagonist, MCPG, had no effect on f-EPSPs but did reduce the effect of ACPD. High-frequency stimulation (50-100 Hz) elicited f-EPSPs that were smaller with each successive stimulus. In ACPD, f-EPSP(1) was 40% smaller than predrug, but f-EPSPs(3-5) were not changed compared to pre-ACPD f-EPSPs(3-5), indicating that ACPD occludes the effect of repetitive stimulation. MCPG increased f-EPSP(5) by 15%, indicating that a portion of the reduction of f-EPSPs during high-frequency stimulation is mediated by mGluRs. MCPG also partially blocked the effect of ACPD. In CNQX, ACPD only decreased EPSPs, but APV or bicuculline did not change the effect of ACPD. These results suggest that the successive reduction of f-EPSPs during a high-frequency train is partially a result of mGluR activation.