Epilepsy: How parasitic larvae affect the brain

The release of the neurotransmitter glutamate by the parasitic tapeworm Taenia solium appears to be implicated in the pathophysiology of a widespread, but neglected, form of adult-onset epilepsy.
  1. Zin-Juan Klaft
  2. Chris Dulla  Is a corresponding author
  1. Department of Neuroscience, Tufts University School of Medicine, United States

Infections caused by the tapeworm Taenia solium are a major source of illness, especially in low- and middle-income countries (Torgerson et al., 2015). When the larvae of this parasite establish cysts in the brain, a condition that is known as neurocysticercosis, the consequences can include seizures and epilepsy. Indeed, neurocysticercosis is among the leading causes of adult-onset epilepsy worldwide (Ta and Blond, 2022; Nash et al., 2013), and a significant fraction (22–29%) of all epilepsy patients in sub-Saharan countries have neurocysticercosis (Owolabi et al., 2020; Ndimubanzi et al., 2010).

Seizures and epilepsy are thought to occur when the cysts burst and release their contents into the brain, and previous research has focused on the role of the brain’s neuroinflammatory response in the development of these conditions (Robinson et al., 2012). Interestingly Taenia solium larvae are thought to actively suppress the local immune response to their own presence, allowing them to reside in the brain for months or even years. However, besides the work on neuroinflammation, there has been little research into the effects of the larvae (and their secretions) on neuronal activity. Now, in eLife , Joseph Raimondo (University of Cape Town) and colleagues – including Anja de Lange and Hayley Tomes as joint first authors – report the results of experiments that explore the impact of larvae on the brain (de Lange et al., 2023). These results are directly relevant to understanding the pathogenesis of acute seizures (ictogenesis) and – since seizures beget seizures – also chronic epilepsy.

The key finding of the new work is that the larvae and their secretions contain a neurotransmitter called glutamate, with the level of glutamate being high enough to directly activate surrounding neurons. To show this, de Lange et al. first homogenized Taenia solium larvae and collected their excretion/secretion products. They then exposed neurons to these products, and showed that this exposure activated the neurons to fire action potentials. Moreover, if glutamate receptors in the neurons were blocked before exposure to the larval products, the neurons were not activated.

The researchers – who are based in Cape Town and at institutions in Australia, France, Germany, the UK and Zambia – then used fluorescent calcium imaging to study how local activation of neurons by the glutamate from the larvae affects local brain circuits. Rises in intracellular calcium are a proxy for neuronal activity, so imaging calcium allows the neuronal activity across brain circuits to be visualized. These imaging experiments confirmed that glutamate from the larvae caused local neuronal activation that led to the subsequent activation of synaptically connected neurons across distal brain circuits. The researchers also investigated other products excreted or secreted by the larvae that could potentially affect the firing of neurons (such as substance P, acetylcholine and potassium), but none of these had the same widespread impact as glutamate. The results were consistent, therefore, with glutamate from the larvae having a potential role in the generation and/or propagation of seizures.

Next, de Lange et al. showed that the larval products showed similar excitatory effects in in vitro brain tissue from both animal models and from resected human brain tissue. They also demonstrated that the glutamate can excite the surrounding brain tissue, which has been shown to drive later epilepsy in other studies (Zeidler et al., 2018). Moreover, it has previously been shown that glutamate released by brain tumors can induce epileptic activity (Buckingham et al., 2011; Sontheimer, 2008), and researchers are exploring ways to target glutamate release in order to prevent such seizures (Ghoochani et al., 2016).

Similar strategies may be beneficial when tackling neurocysticercosis to reduce seizures, or possibly even prevent the development of chronic epilepsy. This is critically important because millions of neurocysticercosis patients suffer from seizures and epilepsy. However, the latest study does not demonstrate that larval products cause seizures or epilepsy, as it was carried out at the level of single cells and small circuits with small volumes (just picoliters) of larval products, so for now we only know how neurocysticercosis leads to neuronal hyperexcitability. Future studies will be needed to understand the effects of larval products, and the larvae themselves, on larger circuits in vivo, and to explore if/how this pathological excitation leads to long-term changes in the brain that cause it to generate spontaneous recurring seizures. Non-glutamatergic mechanisms, including neuroimmunological processes, may also still be relevant to these changes.

This study moves the field closer to understanding epilepsy in human neurocysticercosis by providing exciting experimental evidence, and by also providing naturalistic, disease-relevant models that will enable the study of novel treatment approaches. It is also important because neurocysticercosis – a condition that disproportionately affects people in low-income and under-resourced countries – has not received sufficient attention in the past. The current findings from Cape Town may just have kickstarted much-needed research in neurocysticercosis by finding out what Taenia solium larvae do to the neuronal networks that surround them. Exciting!

Neurocysticercosis and epilepsy.

Taenia Solium is a parasite that can infect the brain and cause neurocysticercosis, which is a prevalent but poorly understood cause of acquired epilepsy. de Lange et al. have shown that Taenia Solium contains significant amounts of a neurotransmitter called glutamate, which can activate neurons and circuits of neurons. Future studies are required to establish a link between Taenia Solium, glutamate and epilepsy, but this study is an important first step in this direction.

References

Article and author information

Author details

  1. Zin-Juan Klaft

    Zin-Juan Klaft is in the Department of Neuroscience, Tufts University School of Medicine, Boston, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8208-7263
  2. Chris Dulla

    Chris Dulla is in the Department of Neuroscience, Tufts University School of Medicine, Boston, United States

    For correspondence
    chris.dulla@tufts.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6560-6535

Publication history

  1. Version of Record published: August 23, 2023 (version 1)

Copyright

© 2023, Klaft and Dulla

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,366
    views
  • 52
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Zin-Juan Klaft
  2. Chris Dulla
(2023)
Epilepsy: How parasitic larvae affect the brain
eLife 12:e91149.
https://doi.org/10.7554/eLife.91149
  1. Further reading

Further reading

    1. Neuroscience
    Ece Kaya, Sonja A Kotz, Molly J Henry
    Research Article

    Dynamic attending theory proposes that the ability to track temporal cues in the auditory environment is governed by entrainment, the synchronization between internal oscillations and regularities in external auditory signals. Here, we focused on two key properties of internal oscillators: their preferred rate, the default rate in the absence of any input; and their flexibility, how they adapt to changes in rhythmic context. We developed methods to estimate oscillator properties (Experiment 1) and compared the estimates across tasks and individuals (Experiment 2). Preferred rates, estimated as the stimulus rates with peak performance, showed a harmonic relationship across measurements and were correlated with individuals’ spontaneous motor tempo. Estimates from motor tasks were slower than those from the perceptual task, and the degree of slowing was consistent for each individual. Task performance decreased with trial-to-trial changes in stimulus rate, and responses on individual trials were biased toward the preceding trial’s stimulus properties. Flexibility, quantified as an individual’s ability to adapt to faster-than-previous rates, decreased with age. These findings show domain-specific rate preferences for the assumed oscillatory system underlying rhythm perception and production, and that this system loses its ability to flexibly adapt to changes in the external rhythmic context during aging.

    1. Neuroscience
    Elissavet Chartampila, Karim S Elayouby ... Helen E Scharfman
    Research Article

    Maternal choline supplementation (MCS) improves cognition in Alzheimer’s disease (AD) models. However, the effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated the effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes [IIS]). IIS also are common in other mouse models and occur in AD patients. In mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor ∆FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore, we studied ΔFosB expression in GCs. We also studied the neuronal marker NeuN within hilar neurons of the DG because reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate, or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ∆FosB expression was reduced, and hilar NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB, and spatial memory in an animal model of AD.