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ToxSci Advance Access published online on June 29, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp141
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Domoic acid induces a long-lasting enhancement of CA1 field responses and impairs tetanus-induced long-term potentiation in rat hippocampal slices

Shenfeng Qiu*,{ddagger}, Azadeh K. Jebelli{dagger}, John H. Ashe*,§ and Margarita C. Currás-Collazo*

* Department of Cell Biology & Neuroscience, University of California, Riverside, CA 92521 {dagger} Department of Psychology, University of California, Riverside, CA 92521

Corresponding author: Dr. Shenfeng Qiu, Department of Pharmacology, Vanderbilt University Medical Center, 8114A MRB III, Nashville, TN 37232, Tel. (615)-936-3662, Email. Shenfeng.qiu{at}vanderbilt.edu

Received April 23, 2009; revision received June 20, 2009; accepted June 22, 2009


  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 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) was 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.

{ddagger} Correspondence Author.

§ Deceased

Current affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232


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