Persistent Neurological Damage Associated With Spontaneous Recurrent Seizures and Atypical Aggressive Behavior of Domoic Acid Epileptic Disease

Abstract

The harmful alga Pseudo-nitzschia sp. is the cause of human amnesic shellfish poisoning and the stranding of thousands of sea lions with seizures as a hallmark symptom. A human case study and epidemiological report of hundreds of stranded sea lions found individuals presenting months after recovery with a neurological disease similar to temporal lobe epilepsy. A rat model developed to establish and better predict how epileptic disease results from domoic acid poisoning demonstrated that a single episode of status epilepticus (SE), after a latent period, leads to a progressive state of spontaneous recurrent seizure (SRS) and expression of atypical aggressive behaviors. Structural damage associated with domoic acid-induced SE is prominent in olfactory pathways. Here, we examine structural damage in seven rats that progressed to epileptic disease. Diseased animals show progressive neuronal loss in the piriform cortex and degeneration of terminal fields in these layers and the posteromedial cortical amygdaloid nucleus. Animals that display aggressive behavior had additional neuronal damage to the anterior olfactory cortex. This study provides insight into the structural basis for the progression of domoic acid epileptic disease and relates to the California sea lion, where poisoned animals progress to a disease characterized by SRS and aggressive behaviors.

Domoic Acid Epileptic Disease

“…The piriform cortex, on the other hand, contains the most sensitive circuits to electrical and chemical induction of seizures and has been proposed to play a central role to intensify the spread of seizures [36,37]. This is consistent with the finding that piriform cortex, which receives direct input from the olfactory bulb via the lateral olfactory tract shows continued damage during maturation of domoic acid epileptic disease [35]. …”

“…Progressive structural damage to the brain is more limited than that found after domoic acid induced status epilepticus [35]. Cupric silver staining, reflective of recent (within several days) neuronal necrosis, was examined to identify ongoing damage in animals that progressed to spontaneous recurrent seizures and/or atypical aggressive behaviors.…”

“…For example, the sensitivity of olfactory vs. hippocampal targets for domoic acid may be more prominent in rodents than in sea lions. However, sea lions show comparable atypical aggressive behavior during domoic epileptic disease as seen in rats, which appears to reflect a deficit in olfactory processing of conspecific recognition [35,49]. Thus closer examination of the olfactory pathways is merited in cases of domoic acid epileptic disease.…”

Preclinical Modeling of Exposure to a Global Marine Bio-Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory

“…At autopsy, this patient showed serious bilateral hippocampal sclerosis. Adult rats exposed to DA also exhibit changing neurological symptomology and after recovery from acute toxicity, enter a period of clinical silence before the onset of progressive, recurrent seizures Ramsdell, 2011, Tiedeken andRamsdell, 2013). In young California sea lions receiving veterinary treatment for DA toxicosis, complete recovery from acute poisoning can be followed by a progressive and frequently lethal epilepsy-like syndrome that is not clinically manifest until months after cessation of exposure (Ramsdell and Gulland, 2014).…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…In piriform cortex a reduced cell density has been noted in the medial layer 3 (1.3-1.8 fold decrease compared to controls), an area that shows also prominent amino cupric staining (stain that assesses neuronal damage) (Tiedeken and Ramsdell, 2013a). The same research group has reported that by following the above experimental procedure but sacrificing the rats 7 days after DomA-induced seizures intense and widespread silver reaction product in the olfactory bulb occurs, whereas minor or no evident damage is found in the hippocampus (Tiedeken et al, 2013b).…”