In my previous posts (Part 1, Part 2) I discussed the relationships between schizophrenia, T. gondii infections and the genetics behind each of those related conditions. As promised, here is a continuation of that discussion in regards to psychosis and cognitive changes in schizophrenia and T. gondii infection.
Psychosis & Cognitive Changes
Dopamine is a neurotransmitter involved in reaching for that dark chocolate accomplice to your afternoon coffee (reward systems) and in doing so without actually spilling your coffee (movement). Yay for dopamine, right? However, a disrupted dopamine system is also a classic finding in schizophrenia and psychosis.
What does this mean? Well there are several different ways to look at this question:
Do increased dopamine levels cause psychosis?
Does psychosis lead to increased levels of dopamine?
Does dopamine act on an intermediate factor which then contributes to psychosis?
Let’s look a little further into that last scenario. Interestingly enough, dopamine appears to increase the ability of Toxoplasma tachyzoites (the life cycle stage of the parasite that reaches the brain) to replicate and then destroy cells in in vitro assays . This was not prevented by adding inhibitors of dopamine .
Once again, there are several ways this relationship between elevated dopamine levels and infection could occur:
Does the infection cause the increased levels of dopamine?
Or could increased dopamine provide an environment conducive to infection, increasing susceptibility?
Research suggests both possibilities could be at play. Studies in mice demonstrate an increase in dopamine upon infection, and research on T. gondii has discovered that this ingenious bug is capable of making its own dopamine and serotonin precursors ! However, it also appears to have an affinity for dopamine-rich areas of the brain, such as the frontal cortex and diencephalon .
Now another element of the toxoplasma-related cognitive change involves glutamate neurotransmission. Glutamate is your major excitatory neurotransmitter. Imagine you want to roast some marshmallows so you build a small fire, carefully confined to a stone-rimmed firepit. The fire is needed and useful when present in the right amount, the right place and the right time. What happens when that fire is too big, gets outside of where it is supposed to be, or doesn’t get put out properly before you leave? You end up with Smokey Bear lectures and a ban on outdoor cooking experiments. Think of glutamate like that fire, it has to be carefully controlled. This is why it is mostly present inside of cells where it is inactive, rather than outside of cells where it is active.
How is glutamate neurotransmission involved in T. gondii infection? This gets a little complicated but in short form, inflammation and infection can lead to increased tryptophan breakdown through the tryptophan/kynurenine pathway. Infection/inflammation (i.e. cytokines, especially IFN-gamma) increases enzymes (IDO/TDO) that lead to more inflammatory breakdown products. Inflammation also affects the HPA axis, which in turn also ramps up these enzymes [2,3]. The resulting inflammation triggers apoptosis, leads to demyelination and is thought to affect glutamate neurotransmission in these ways [4,5]:
Elevated kynurenic acid (inflammatory breakdown product) is an antagonist to the NMDA (glutamate) receptors in the brain.
Antibodies cross-react between T. gondii and NMDA receptors.
Infection could lead to a downregulation of NMDA receptors.
Basically, these all relate to inhibiting glutamate receptors. This inhibition is associated with both positive (hallucinations, delusions) and negative (catatonia) symptoms of schizophrenia.
And yes, as might be expected according to these studies, patients with schizophrenia and Toxoplasma infections do have a more continuous disease course and more severe positive symptoms than patients with schizophrenia but no infection [5,6].
Looking more on the immune side of the equation, the behavioural patterns seen in schizophrenia may also be partly explained by heightened levels of C1q (a component of the classical complement pathway) in the brain . The complement system is like the immune system’s rule system for incoming emails. It looks at the subject (antigens on the invading bug) and marks it for destruction if it is problematic (junk mail). Pieces of this system not only interact with the cysts in latent T. gondii infections but it may also create a loss in synapses and neurons .
(Nerd note: Going back to genetic associations for a minute, consider that there are alleles that result in increased C4 levels (C4A specifically), that these alleles are associated with schizophrenia, and that C4 works with C1q in the complement pathway .)
In terms of neuroanatomical changes, a unique feature to schizophrenic patients with infections as opposed to those without is a decrease in grey matter density in areas of the caudate, cingulate, thalamus, occipital cortex and cerebellum .
Pet cats aren’t the only way to come into contact with Toxoplasma. I’m really not intending to incite a witch-hunt against cats. Cats are an important part of the T. gondii life cycle, but the protozoa can be spread from faeces via insects, etc. We can also become infected through contact with contaminated soil (gardening, etc), unwashed fruits and vegetables, or consumption of undercooked meat . Infected cats also only shed the oocysts for a couple weeks, although these can persist in the environment in harsh conditions for longer periods of time .
In addition, Toxoplasma isn’t the only infectious agent linked to symptoms such as those seen in schizophrenia. Is there not more than one cause for a headache? Is it not then plausible to have multiple causes for psychosis? To further complicate matters, coinfections such as T. gondii and H. pylori may team up to create a greater risk for cognitive impairment . All in all, it’s a complicated picture, especially once you start looking at other factors beyond infectious agents (i.e. gluten-induced psychoses, etc.).
The goal here was simply to highlight an important biological trigger for a “psychological” disorder. Links to infectious agents can be found in other “psychological” disorders as well and in recognition of this we need to be more mindful to evaluate all aspects of a patient’s history before resigning them to a DSM diagnosis. Furthermore, establishing connections to infectious agents will enable better-directed efforts at prevention and research into treatment. There currently is no treatment for latent toxoplasmosis .
Keep an eye out for the related recipe to this series on T. gondii and psychosis: Cat-Crazed Carnitas!
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