Fetal domoic acid exposure affects lateral amygdala neurons, diminishes social investigation and alters sensory-motor gating

Abstract

Domoic acid (DA) is an algal neurotoxin that accumulates in marine fish and shellfish. DA can move across the placenta and concentrate in amniotic fluid, which can be swallowed during late gestation. DA also transfers to infants via milk. Preclinical studies to determine effects of developmental DA expose have primarily involved DA exposure during the postnatal period and little is known about late CNS effects following prenatal DA. In the present study, we tested the hypothesis that prenatal exposure of FVB mice to low levels of DA would result in diminished social interaction and sensory motor gating associated with alterations in parvalbumin immunoreactivity in relevant brain regions undergoing development during and following DA exposure. In addition to parvalbumin, we stained with NeuN for a neuronal specific nuclear protein to determine if neuronal loss followed prenatal DA exposure. A single moderate dose of DA administered during gestation produces diminishes social investigation and alters sensorimotor gating, behavioral effects more pronounced in males than females. These behavioral changes were associated with discrete alterations in the parvalbumin-positive subtype of GABAergic neurons in the dentate gyrus and lateral amygdala.

Prenatal domoic acid exposure disrupts mouse pro-social behavior and functional connectivity MRI

“…We also found a trend toward lower USV production, suggesting a relationship between social investigation and USV production that we have noted previously [80, 81]. Effects of DA on adolescent social investigation by B6 mice are modest in the current report and are similar to our previous studies with FVB mice [65]. Our finding of DA effects on adolescent social behavior is consistent with the juvenile onset of social deficits diagnosed in autism [82].…”

“…To engage these receptors in regions outside the time and place of hippocampal neurogenesis, we injected a single dose to DA (1.5 mg/kg) to pregnant B6 dams on ED16. Exposure at this dose and developmental timepoint diminshes social investigation in adolescent FVB mice and results in an increase in parvalbumin immnoreactivity, an anatomical finding that suggests DA exposure dysregulates excitatory/inhibitory tone [65]. We do not know how DA disrupts mouse social behavior because prenatal exposure to straddling timepoints, ED14.5 and ED17.5, which also causes profound changes in conditioned fear memory and adaptation to novel circumstances, effects myelination and growth of neuronal processes [20].…”

“…When at a weight of 30 grams (M = 30.157 grams, SD = 1.513), embryonic day (ED) 16 (M = 16.2, SD = 1.66), gravid females were injected subcutaneously with either 1.5 mg/kg of DA or saline. We chose this dose of DA based upon results of our own experimental evidence that exposure to this dose causes deficits in adolescent social approach behavior in FVB mice [65] and based upon evidence of effectiveness in comparable doses of DA administered via intraperitoneal injection [20] and below the threshold expected to induce convulsive effects or inducing fetal loss [66]. Weaning occurred on postnatal day (PD) 20-22; pups were separated by sex and placed in separate clean colony cages.…”

What California sea lions exposed to domoic acid might teach us about autism: lessons for predictive and preventive medicine

“…Critically, variations in excitatory tone are associated with deficits in social functioning [61] and in heightened seizure susceptibility [54,[62][63][64]. Exposure to toxic levels of DA and ASD also share in common abnormalities in limbic structures [64,65], particularly the hippocampus [66][67][68][69] and the amygdala [64,70,71], along with possible similarities in connectivity [72,73]. Lesions in the hippocampus and amygdala are a prominent feature of autopsies from brains of DA-exposed humans, rodents, and DAexposed marine mammals [64,66,67].…”

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

“…Despite cessation of DA exposure at birth, progressive damage to regions of the hippocampus have been documented over the first 30 days of postnatal life (Dakshinamurti et al, 1993). Results from a number of studies suggest that a single in-utero exposure can cause long-term changes in behavioral development, primarily targeting cognition, social behavior and emotionality and experimental results are frequently accompanied by gender-related differences in performance (Levin et al, 2005, Doucette et al, 2007Adams et al, 2008;Burt et al, 2008;Tanemura et al, 2009, Ryan et al, 2011Gill et al, 2012;Marriott et al, 2012, Zuloaga et al, 2016, Shiotani et al, 2017. Early postnatal exposure is associated with a time-dependent profile of neurotoxicity that is characterized by hyperactivity, stereotypic scratching, convulsions and death (Xi et al, 1997).…”