Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission

Abstract

This overview tries to bridge the gap between psychoneuroimmunological findings and recent results from pharmacological, neurochemical and genetic studies in schizophrenia. Schizophrenia is a disorder of dopaminergic neurotransmission, but modulation of the dopaminergic system by glutamatergic neurotransmission seems to play a key role. This view is supported by genetic findings of the neuregulin- and dysbindin genes, which have functional impact on the glutamatergic system. Glutamatergic hypofunction, however, is mediated by the N-methyl-D-aspartate (NMDA)-receptor antagonism. The only endogenous NMDA receptor antagonist identified up to now is kynurenic acid (KYNA). Despite the NMDA receptor antagonism, KYNA also blocks, in lower doses, the nicotinergic acetycholine receptor, i.e., increased KYNA levels can explain psychotic symptoms and cognitive deterioration. KYNA levels are described to be higher in the cerebrospinal fluid (CSF) and in critical central nervous system (CNS) regions of schizophrenics as compared to controls. Another line of evidence suggests that a (prenatal) infection is involved in the pathogenesis of schizophrenia. Due to an early sensitization process of the immune system or to a (chronic) infection, which is not cleared through the immune response, an immune imbalance between the type-1 and the type-2 immune responses takes place in schizophrenia. The type-1 response is partially inhibited, while the type-2 response is over-activated. This immune constellation is associated with inhibition of the enzyme indoleamine dioxygenase (IDO), because IDO - located in astrocytes and microglial cells - is inhibited by type-2 cytokines. IDO catalyzes the first step in tryptophan metabolism, the degradation from tryptophan to kynurenine, as does tryptophan 2,3-dioxygenase (TDO). Due to the inhibition of IDO, tryptophan-kynurenine is predominantly metabolized by TDO, which is located in astrocytes, not in microglial or other CNS cells. In schizophrenia, astrocytes in particular are activated, as increased levels of S100B appear. Additionally, they do not have the enzymatic equipment for the normal metabolism-route of tryptophan. Due to the lack of kynurenine hydroxylase (KYN-OHase) in astrocytes, KYNA accumulates in the CNS, while the metabolic pathway in microglial cells is blocked. Accordingly, an increase of TDO activity has been observed in critical CNS regions of schizophrenics. These mechanisms result in an accumulation of KYNA in critical CNS regions. Thus, the immune-mediated glutamatergic-dopaminergic dysregulation may lead to the clinical symptoms of schizophrenia. Therapeutic consequences, e.g., the use of anti-inflammatory cyclo-oxygenase-2 inhibitors, which can also decrease KYNA directly, are discussed.

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

“…However, studies using cultured microglial cells have shown effects of activation and production of inflammatory mediators in response to these cytokines (36)(37)(38). In addition, there is compelling evidence indicating that these cytokines may be involved in the neuropathology of schizophrenia (39,40). The present study showing increased levels of IL-4 and IL-13 transcription in the orbitofrontal cortex of suicides suggests that these cytokines may affect neurobehavioral processes relevant to suicide.…”

“…The latter relates to the activation or inhibition of the IDO enzyme that will ultimately result in altered serotonin metabolism and production of neuroactive substances. For reviews on these issues see (39)(40)(41)(42).…”

The Future of Mental Health Care Toward an Integrative Paradigm

“…Some novel approaches in medicine and psychiatry do not radically depart from assumptions embedded in the orthodox views of conventional biomedicine. For example psychoneuroimmunology (PNI) is a synthetic model that starts from established theories in psychiatry and biomedicine and postulates complex www.intechopen.com dynamic relationships between stress, immunological status and psychiatric or neurological symptom formation Muller & Schwarz 2007;Muller & Schwarz 2006). There is a rich discussion of PNI and other emerging paradigms in the peer-reviewed journal literature including emerging models in physics, biology and information science describing structure-function relationships in complex living systems.…”

“…Recent studies suggest that nonspecific over-activation of the immune system involving T-helper cells takes place in subgroups of persons with schizophrenia (Strous & Shoenfeld 2006). The immune-mediated dysregulation of both dopamine and glutamate neurotransmission has also been implicated in the pathogenesis of schizophrenia (Muller & Schwarz 2006). In response to these findings, anti-inflammatory and immune-modulating therapies are being investigated as future treatments for affective disorders and schizophrenia.…”

Development and characterization of chronic animal models of schizophrenia

“…Several neurotransmitter abnormalities such as the dopaminergic, glutamatergic (GLU), GABAergic (γ-aminobutyric acid) deficits play important roles in schizophrenia [19,20].…”