Developmental exposure to domoic acid disrupts startle response behavior and circuitry

Jennifer M. Panlilio, Ian T. Jones, Matthew C. Salanga, Neelakanteswar Aluru, Mark E. Hahn

Preprint posted on January 13, 2021

“Startling” findings reveal algae bloom toxin induces neurological cellular defects

Selected by Kirsten C. Sadler, Patrice Delaney

Context and background

A marine algal bloom occurs when a single species of algae rapidly expands due to enrichment of nutrients, with industrial farming and rising global temperatures as two leading culprits [2]. Alarmingly, algae bloom frequency, severity and geographical span has steadily increased over the past three decades [3]. Blooms can be catastrophic for the ecosystems they dominate and can cause direct harm to humans since some algae species produce toxins that cause illnesses and, in extreme cases, fatalities [4]. Further, a single occurrence of a harmful algae bloom can have long-lasting and far-reaching effects due to toxin bioaccumulation in shellfish which then can be passed to the humans that consume them [5].

Pseudo-nitzschia is a diatom that is prone to blooms, most famously on the North American West Coast. Consuming fish and shellfish that ingest Pseudo-nitzschia poses a serious risk of contracting Amnesic Shellfish Poisoning. This is due to the diatom’s production of domoic acid (DomA), an analog of the neurotransmitter glutamate [6]. Current regulations deem 20 mg of DomA per kg of shellfish tissue as acceptable for consumption [7], however, developmental exposure to low doses of DomA has been linked to neurological defects, including seizures, memory impairment, and limbic system degeneration in both humans and animal models [5, 8]. Notably, the effects of subclinical exposure to DomA can manifest in later life, synergizing with aging, secondary neurological toxicants, or disorders [9]. While the effects of DomA exposure are well characterized, the cellular and molecular mechanisms underlying clinical manifestations are unknown.

The paper, “Developmental exposure to domoic acid disrupts startle response behavior and circuitry”, utilizes the zebrafish model to assess how early life exposure to low doses of DomA causes neurological cellular anomalies corresponding to DomA induced behavioral phenotypes. Zebrafish provide an ideal model to examine the behavioral, cellular, and molecular effects of DomA exposure. Previous work from the authors using this model showed that DomA exposure causes behavioral defects characterized by impairment of the startle response, while the current study focuses on identifying the specific neuronal cell populations and circuitry that are disrupted by DomA exposure. The authors hypothesize that DomA exposure eliminates or impairs the neurons that coordinate the startle response and employed imaging, cellular neurobiology and behavioral assays to identify the cell populations sensitive to DomA.


Key Findings

1. DomA exposure impairs the startle response in larval zebrafish

Zebrafish exposed to low doses of DomA (0.14 ng) intravenously on 2 two days post fertilization (dpf) exhibited defects in the startle response at 7 dpf compared to control siblings injected with a saline solution. Specifically, the short-latency startle response, which is a quick, pronounced bend upon auditory or vibration stimuli, was significantly reduced in DomA treated fish. The benefits of the large sample size in zebrafish permit examining the response across a large number of individual animals. The authors noted that some DomA treated fish had nearly normal startle responses, and these were characterized by a normal myelin sheath, whereas those with greater severe myelin sheath deficits were more severely impaired in their short latency startle response.


2. DomA induced behavioral defects cannot solely be attributed to lack of stimuli detection 

Direct-electric field stimuli, which bypasses the sensory input networks and instead activates sensorimotor neurons, determined that the short-latency startle response is reduced in DomA treated larvae. This suggests the loss of the startle response by DomA cannot be solely attributed to sensory input defects, but rather due to a deficit in downstream sensorimotor neurons, such as Mauthner cells which receive input from ganglia cranial nerve synapses and propagate this signal down the spinal cord to the motor neurons, triggering a physical response [10].


3. DomA exposure prevents proper development of a subset of sensorimotor neurons

Since Mauthner cells are an essential component in orchestrating the short-latency startle response, the authors focused their investigation on these cells. Confocal imaging of 5 and 7 dpf DomA treated and control zebrafish larvae revealed that Mauthner cells were absent in DomA treated larvae. Further, the neuromasts and input sensory neurons appeared normal, suggesting that the behavioral phenotype is due to loss of downstream motor neurons rather than an inability to detect stimuli.


Figure 1. Author’s graphical abstract [1]. Developmental exposure to DomA in zebrafish larvae inhibits normal circuitry networks which are essential for coordination of the startle response. Specifically, loss of Mauthner cells (teal), as well as reduced branching in motor neurons (maroon), prevent physical responses to stimuli.



Why this preprint

Although the clinical phenotypes of developmental exposure to DomA are well established, the underlying cellular defects that cause these behavioral effects are unknown. Such findings are vital for future efforts to identify and treat patients that have been exposed to DomA. This preprint utilizes the strengths of the zebrafish model to present novel findings into the cellular basis for DomA induced phenotypes. Their images are striking and high quality, allowing nonexperts to easily spot the phenotypic outcomes of DomA exposure at the cellular level. This work shows that DomA abolishes sensorimotor neurons, which can prevent downstream responses to stimuli, providing a strong mechanistic framework for future studies. Moreover, global warming has caused an increase in algal blooms worldwide [2, 3] and it is anticipated that these massive ecological disturbances will pose an increasing threat to human health.


Open questions


  1. The authors conclude in their discussion that this study does not fully explore the contribution of sensory input defects in DomA induced phenotypes. Although the sensory neurons are present and appear normal in DomA treated larvae, these neurons can still be inoperative. To rule out defects in the sensory input system, future studies in other animal models should explore axon firing in these nerves compared to downstream motor neurons to determine the range of DomA induced abnormalities in neuron networks. This will aid in identifying neuronal cells that are most vulnerable to DomA exposure.


  1. The author’s previous studies identified a window of DomA susceptibility in zebrafish larvae at 2 dpf. This study shows that low dose exposure to DomA at 2 dpf prevents establishment of Mauthner cells. To better understand how DomA impacts Mauthner cells and primary motor neurons branching, it would be interesting to explore the developmental fate and function of these cells in larvae exposed to DomA prior to or after their formation. This will help determine to what extent DomA causes atrophy of Mauthner cells or has an inhibitory effect on their development.


  1. One of the strengths of the zebrafish model is that it is amendable to high-throughput drug screens. Larvae can be cultured in 96-well plates and drug treatment is as simple as adding them to the culture water. Exploring how subtoxic doses of DomA at 2 dpf synergize with candidates from libraries of FDA molecularly characterized drugs would be beneficial for identifying targets that amplify or reduce DomA induced phenotypes. Such studies would provide mechanistic insights into how DomA causes motor neuron defects as well as identify new therapeutic targets.


  1. Finally, it is important to identify the underlying molecular mechanism by which DomA leads to cell loss of Mauthner cells. Is it through stimulating the glutamate receptor? Further exploration of glutamate signaling in this cell type might provide insights into how DomA disrupts these cells.




  1. Panlilio JM, Jones IT, Salanga MC, Aluru N, Hahn ME: Developmental exposure to domoic acid disrupts startle response behavior and circuitry. bioRxiv 2021:2021.2001.2008.425996.
  2. Gobler CJ: Climate Change and Harmful Algal Blooms: Insights and perspective. Harmful Algae 2020, 91:101731.
  3. Ho JC, Michalak AM, Pahlevan N: Widespread global increase in intense lake phytoplankton blooms since the 1980s. Nature 2019, 574(7780):667-670.
  4. Trevino-Garrison I, DeMent J, Ahmed FS, Haines-Lieber P, Langer T, Ménager H, Neff J, van der Merwe D, Carney E: Human illnesses and animal deaths associated with freshwater harmful algal blooms-Kansas. Toxins (Basel) 2015, 7(2):353-366.
  5. Lefebvre KA, Robertson A: Domoic acid and human exposure risks: A review. Toxicon 2010, 56(2):218-230.
  6. Bates SS, Hubbard KA, Lundholm N, Montresor M, Leaw CP: Pseudo-nitzschia, Nitzschia, and domoic acid: New research since 2011. Harmful Algae 2018, 79:3-43.
  7. Wekell JC, Jurst J, Lefebvre KA: The origin of the regulatory limits for PSP and ASP toxins in shellfish. J Shellfish Res 2010, 23:927-930.
  8. Shiotani M, Cole TB, Hong S, Park JJY, Griffith WC, Burbacher TM, Workman T, Costa LG, Faustman EM: Neurobehavioral assessment of mice following repeated oral exposures to domoic acid during prenatal development. Neurotoxicology and Teratology 2017, 64:8-19.
  9. Hesp BR, Clarkson AN, Sawant PM, Kerr DS: Domoic acid preconditioning and seizure induction in young and aged rats. Epilepsy Res 2007, 76(2-3):103-112.
  10. Mirjany M, Preuss T, Faber DS: Role of the lateral line mechanosensory system in directionality of goldfish auditory evoked escape response. The Journal of Experimental Biology 2011, 214(20):3358.


Posted on: 22nd March 2021


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