domoic-acid and Memory-Disorders

To demonstrate induction of delayed central nervous toxicity by disturbing neuronal activities in the developing brain, we administered a single intraperitoneal dose of domoic acid (DA; 1 mg/kg), a potent glutamate receptor agonist, to pregnant female mice at the gestational day of 11.5, 14.5 or 17.5. The dams had recovered from acute symptoms within 24 hr, followed by normal delivery, feeding and weaning. All male offspring mice after weaning were apparently normal in response to handlers during cage maintenance, body weight measurement and to mate mice in group housing conditions. At the age of 11 weeks, our neurobehavior testing battery revealed severe impairment of learning and memory with serious deviances of anxiety-related behaviors. The developed brain of prenatally exposed mice showed myelination failure and the overgrowth of neuronal processes of the limbic cortex neurons. This study indicates that the temporal disturbance of neurotransmission of the developing brain induces irreversible structural and functional damage to offspring which becomes monitorable in their adulthood by a proper battery of neurobehavioral tests.

Topics: Animals; Anxiety Disorders; Brain; Brain Damage, Chronic; Demyelinating Diseases; Excitatory Amino Acid Agonists; Female; Injections, Intraperitoneal; Kainic Acid; Learning Disabilities; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Morphogenesis; Pregnancy; Prenatal Exposure Delayed Effects; Synaptic Transmission

Topics: Adolescent; Adult; Aged; American Indian or Alaska Native; Animals; Bivalvia; Cohort Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Humans; Kainic Acid; Male; Memory Disorders; Middle Aged; Neuromuscular Depolarizing Agents; Shellfish Poisoning; Young Adult

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.

Topics: Animals; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Electrophysiology; Enzyme Activation; Excitatory Postsynaptic Potentials; Hippocampus; In Vitro Techniques; Kainic Acid; Long-Term Potentiation; Male; Memory Disorders; Neuromuscular Depolarizing Agents; Neuronal Plasticity; Phosphorylation; Protein Kinases; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Tetanus

Single injections of domoic acid, given either intraperitoneally to mice or directly into the hippocampal formation of rats, have been shown to impair learning on the place version of the Morris water maze task and the eight arm radial maze task. The present study was designed to test whether both single and repeated exposures of intraperitoneally administered domoic acid (1.0 or 2.0 mg/kg) impair spatial working memory in mice on a delayed matching-to-sample task. DBA strain mice were given a series of four injections over a 7-day period consisting of either saline or one of two doses of domoic acid. During the 18 days of testing, each subject was given one trial per day consisting of one information run, followed by three test runs. On non-alternation days (days in which the correct response was the same as the preceding day) the saline injected group significantly outperformed the single injection 2.0 mg/kg domoic acid group. This indicates that domoic acid-treated animals were incapable of forming a memory that persisted for 24 h and hence were less able to utilize the prior day's experience. However, the repeated exposure groups did not perform as poorly on non-alternation days than the single exposure groups, indicating that domoic acid may affect multiple mechanisms involved in memory consolidation.

Topics: Animals; Behavior, Animal; Brain; Drug Administration Schedule; In Vitro Techniques; Injections, Intraperitoneal; Kainic Acid; Male; Maze Learning; Memory Disorders; Mice; Random Allocation; Time Factors

The effects of a novel vasopressin fragment analog NC-1900 (pGlu-Asn-Ser-Pro-Arg-Gly-NH2 acetate) were studied on learning and/or memory impairment in passive avoidance task and on cell damage of cultured cerebro-cortical neurocytes induced by glutamic acid. A small dose of NC-1900 (1 ng/kg, s.c.) ameliorated impairments of learning and/or memory induced by intracisternal injection of 467.6 micrograms of 10 microliters glutamic acid. NC-1900 also ameliorated the impairments induced by intracisternal NMDA, AMPA-antagonist CNQX and by metabotropic receptor (mGluR1) agonist 3,5-dihydroxyphenylglycine but not by kainate agonist domoic acid nor MK-801 in mice. NC-1900 (100 pM, 1nM) ameliorated the cell damage of cultured rat cerebro-cortical neurocytes induced by 100 and 1000 microM of glutamic acid. These results suggest that NC-1900 may serve as a remedies in various patients with certain brain disorders induced by excess glutamic acid.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Arginine Vasopressin; Avoidance Learning; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Kainic Acid; Learning Disabilities; Male; Memory Disorders; Mice; Mice, Inbred Strains; N-Methylaspartate; Neuromuscular Depolarizing Agents; Oligopeptides; Pyrrolidonecarboxylic Acid; Rats; Rats, Sprague-Dawley; Resorcinols

In Canada in late 1987 there was an outbreak of an acute illness characterized by gastrointestinal symptoms and unusual neurologic abnormalities among persons who had eaten cultivated mussels. Health departments in Canada solicited reports of this newly recognized illness. A case was defined as the occurrence of gastrointestinal symptoms within 24 hours or of neurologic symptoms within 48 hours of the ingestion of mussels. From the more than 250 reports received, 107 patients met the case definition. The most common symptoms were vomiting (in 76 percent of the patients), abdominal cramps (50 percent), diarrhea (42 percent), headache, often described as incapacitating (43 percent), and loss of short-term memory (25 percent). Nineteen patients were hospitalized, of whom 12 required intensive care because of seizures, coma, profuse respiratory secretions, or unstable blood pressure. Male sex and increasing age were associated independently with the risks of hospitalization and memory loss. Three patients died. Mussels associated with this illness were traced to cultivation beds in three river estuaries on the eastern coast of Prince Edward Island. Domoic acid, which can act as an excitatory neurotransmitter, was identified in mussels left uneaten by the patients and in mussels sampled from these estuaries. The source of the domoic acid appears to have been a form of marine vegetation, Nitzschia pungens, also identified in these waters in late 1987. The contaminated mussels from Prince Edward Island were removed from the market, and no new cases have occurred since December 1987. We conclude that the cause of this outbreak of a novel and severe intoxication was the ingestion of mussels contaminated by domoic acid, a potent excitatory neurotransmitter.

Topics: Adult; Age Factors; Aged; Animals; Bivalvia; Brain Diseases; Canada; Disease Outbreaks; Female; Follow-Up Studies; Food Contamination; Foodborne Diseases; Gastrointestinal Diseases; Humans; Kainic Acid; Male; Marine Toxins; Memory Disorders; Middle Aged; Neurotransmitter Agents; Prince Edward Island; Sex Factors

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.

Topics: Animals; Bivalvia; Brain; Disease Outbreaks; Electromyography; Food Contamination; Glucose; Humans; Kainic Acid; Marine Toxins; Memory Disorders; Motor Neurons; Myoclonus; Necrosis; Nervous System Diseases; Neuromuscular Diseases; Neurotransmitter Agents; Prince Edward Island; Seizures; Temporal Lobe; Tomography, Emission-Computed

Topics: Animals; Bivalvia; Humans; Kainic Acid; Marine Toxins; Memory Disorders; Neurotoxins; Shellfish Poisoning