ToxSci Advance Access originally published online on June 29, 2009
Toxicological Sciences 2009 111(1):140-150; doi:10.1093/toxsci/kfp141
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Domoic Acid Induces a Long-Lasting Enhancement of CA1 Field Responses and Impairs Tetanus-Induced Long-term Potentiation in Rat Hippocampal Slices
* Department of Cell Biology & Neuroscience
Department of Psychology, University of California, Riverside, California 92521
2 To whom correspondence should be addressed at Department of Pharmacology, Vanderbilt University Medical Center, 8114A MRB III, Nashville, TN 37232. Fax: 615-322-5910. E-mail: shenfeng.qiu{at}vanderbilt.edu.
Received April 23, 2009; accepted June 22, 2009
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Abstract |
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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 
-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.
Key Words: AMPA; kainate; amnesia; glutamate receptor; PKA; CaMKII.
1 Present address: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232.