Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression.
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.
CRC, Rm 30, Glasgow, Scotland, United Kingdom.
George
G
Anderson
Michael
M
Maes
D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007239:Infections / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012559:Schizophrenia / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D014364:Tryptophan / Q000502:physiology*
D016207:Cytokines; D016194:Receptors, N-Methyl-D-Aspartate; D014364:Tryptophan