ABSRACT Several large epidemiological studies have found an association between persistent infections (e.g CMV, HSV1, Toxoplasma gondii) and poor performance on indices of cognition such as reaction time or digit span tests. There is also growing interest in the possible role of infections in the cognitive profile of schizophrenia (SCZ). However, there is a need to test specific biological mechanisms that link persistent infections and dysregulated immune mechanisms to SCZ-related negative symptoms and cognitive deficits. The cytokine interferon gamma (IFNg), produced by peripheral immune cells as well as glia, plays a crucial role in controlling persistent neurotropic pathogens and in mediating the communication between the immune and nervous systems. A primary mechanism of IFNg is the shunting tryptophan degradation along the kynurenine (KYN) pathway through an enzyme-controlled series of steps. This causes the elevation KYN and kynurenic acid (KYNA) levels. KYNA in turn acts as an antagonist at two key neurotransmitter receptors: the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the alpha-7 nicotinic acetylcholine (a7nACh) receptor. Moreover, the effect of a newly discovered receptor for KYNA, G-protein linked receptor 35 (GPR35), has not yet been investigated for its contribution to schizophrenia-related cognitive deficits.
The aims of this grant are to examine specific neuroimmune mechanisms that underlie the apparent association of infections and certain cellular receptors in the cognitive and negative symptoms of schizophrenia. We focus on well-defined psychophysiological indices and cognitive tests to examine IFNg activation, and an imbalance in the KYN-related ligands and GPR35 receptors in the cognitive deficit endophenotype of schizophrenia.
Schizophrenia is a severe mental illness affecting about 1% of the population. The cognitive impairments seen in this disorder create impairments in everyday functioning, for which currently available treatments are inadequate. This project will generate new knowledge regarding immune related mechanisms that underlie impaired cognition in schizophrenia, so that novel and hopefully more effective treatments can be developed.
