Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression.

Prog Neuropsychopharmacol Biol Psychiatry. 2013 Apr 5;42:5-19.

Anderson G, Maes M.

CRC, Rm 30, Glasgow, Scotland, United Kingdom.



In 1995, the macrophage-T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno-inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl d-aspartate receptor (NMDAr) and glutamate production. The aim of the present paper is to review the current state-of-the art regarding the role of the above pathways in schizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno-inflammatory pathways coupled to increased microglia activation. The ensuing activation of immuno-inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increased kynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the α7 nicotinic acetylcholine receptor, lowers gamma-amino-butyric-acid (GABA)ergic post-synaptic current, contributing to dysregulated glutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in early development and will interact with these early developmental driven changes in the immuno-inflammatory and TRYCAT pathways. Maternal infection and subsequent immuno-inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno-inflammatory pathways may constitute a double hit on their own, stimulating wider immuno-inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic-induced changes in immuno-inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia-neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance. Copyright © 2012 Elsevier Inc.

PMID: 22800757



In 1995, the macrophage – T lymphocyte theory of schizophrenia was launched (Smith and Maes, 1995) considering that activated immune-inflammatory pathways may explain the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of neuro-inflammation, oxidative and nitrosative stress (O&NS), cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N-methyl D-aspartate receptor (NMDAr) and glutamate production. Schizophrenic patients additionally show lowered levels of endogenous anti-cytokines, e.g. Clara cell protein (CC16), increasing the vulnerability to develop the above-mentioned immune-inflammatory disorders (Maes et al., 1996).

An early developmental model of schizophrenia coupled to a genetic, epigenetic or environmental second ‘hit’ incorporates much of the data on this complex psychiatric disorder. Schizophrenia is also strongly associated with depression, with some studies showing a previously undiagnosed depression in up to 61% of schizophrenia patients (reviewed in Anderson et al, 2013). O&NS coupled to stress and immuno-inflammatory cytokine induced tryptophan 2,3-dioxygenase (TDO) and Indoleamine 2,3-dioxygenase (IDO), by driving tryptophan away from serotonin, N-acetylserotonin and melatonin will contribute to increased depression in schizophrenia, as occurs from the activation of these pathways in other medical conditions (Anderson and Maes, in press-a), including Parkinson’s disease (Anderson and Maes, in press-b). This is important as it suggests that depression is not so much a comorbidity of these psychiatric and neurodegenerative conditions, but rather is an integral part of the etiology, course and treatment of these conditions (Maes et al, 2011).

The increased O&NS and immune-inflammatory processes, intrinsic to the disorders per se, are heightened by associated depression, which contributes to lipid peroxidation and plasma membrane damage, leading to the exposure of previously hidden epitopes, in turn driving an autoimmune response. As such the nature of the immune response changes over the course of these depression associated conditions, including schizophrenia. This links to recent conceptualizations of schizophrenia, bipolar disorder and depression as neuroprogressive disorders (Berk, 2009; Anderson and Maes, in press-c). Neuroprogression pertains to the changes in the biological underpinnings of these conditions over time, including increased levels of apoptosis, decreased neurogenesis and neuroplasticity and neurodegenerative processes as well.

Many of the peripheral, as well as central, influences on central processing are integrated within astrocytes, which then have a regulatory, and sometimes controlling, role on neuronal functioning and survival, including in schizophrenia (Anderson, 2011). Recently we have proposed that astrocyte interactions with neuronal progenitors are also crucial to neurogenesis (Anderson and Maes, in press-d). As such O&NS, activated immune-inflammatory and TRYCAT pathways induced by TDO and IDO highlight the importance of immune driven factors in the etiology and course of schizophrenia and other medical conditions, with effects being mediated, at least partly, via changes in glia regulation of neuronal activity.



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