Schizophrenia (SCZ) is thought to arise from the cumulative interacting effects of genetic and environmental factors. Evidence for infection with the intracellular parasite Toxoplasma gondii (TOXO) in the pathogenesis of SCZ has accumulated over several decades. Two recent meta-analyses found a highly significant elevation in the rate of chronic TOXO infection in SCZ. Humans and rodents are intermediate hosts for TOXO, which evolved a complex lifecycle and unique mechanisms to evade destruction by the host, alter host behavior, and continue its existence. TOXO is neuroinvasive, and the majority of people infected are expected to harbor T. gondii cysts in their brains for life but the parasite does not typically cause overt neurological symptoms in persons with normal immune systems. TOXO is kept in check by an ongoing immune response in which the cytokine interferon gamma (IFN?) plays a critical role. IFN? is produced by several immune cells as well as brain glial cells and prevents TOXO replication by depletion of the amino acid tryptophan (Trp) that TOXO must derive from the host. IFN? achieves local Trp depletion by shunting Trp degradation along the kynurenine (KYN) pathway through an enzyme-controlled series of steps into KYN and kynurenic acid (KYNA). KYNA in turn is an antagonist at two neurotransmitter receptors that are believed to play a key role in SCZ: the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and the alpha7 nicotinic acetylcholine (a7nACh) receptor. Thus there is a plausible mechanism by which TOXO could cause neurochemical abnormalities leading to SCZ, but the preferential activation of the KYN pathway has not yet been demonstrated in SCZ patients with known TOXO infection. Furthermore, a growing literature indicates that there are elevated levels of KYNA in the brains of SCZ patients, although the TOXO status of these patients has not been investigated. TOXO evolved to induce subtle behavioral dysfunction causing infected rodents to have reduced fear of cats and psychomotor slowing. In SCZ patients who are TOXO positive our pilot data indicate slowing of neural processing as indexed by prolongation of latency of the acoustic startle response, and impairment on cognitive testing. This project will investigate the hypothesis that chronic TOXO infection in SCZ leads to immune mediated activation of the KYN pathway, and that this pathway activation is associated with slowing of neural processing and cognitive deficits seen in TOXO positive SCZ. To achieve the following Aims we will assess SCZ patients and healthy controls in our VA cohort for TOXO immunoglobulin G antibody (IgG) antibody titers and plasma levels of kynurenine metabolites and IFN?. We will examine the relationship of these neuroimmune biomarkers and acoustic startle responses, P50 gating, and cognitive function test scores by comparing four groups of 38 subjects per group): 1) TOXO-positive SCZ, 2) TOXO-negative SCZ, 3) TOXO-positive controls, 4) TOXO-negative controls. We also propose new preliminary analyses of KYN pathways in plasma and CSF.
Spec Aim 1 : Measure activation of the KYN pathway in SCZ subjects who are TOXO seropositive compared to TOXO-negative SCZ and control (CON) subjects with and without TOXO. Activation of this pathway will be tested by assays of KYN, KYNA, tryptophan (Trp), and the cytokine IFN?, which induces KYN metabolism. Exploratory Aim 1a: Examine the correlation between plasma and cerebrospinal fluid (CSF) levels of KYN pathway measures in paired historical samples. We hypothesize that plasma and CSF measures will be significantly correlated.
Spec Aim 2 : Test the effect of TOXO infection on neural processing speed as indexed by acoustic startle latency, on impaired P50 gating, and on cognitive function in SCZ compared to CON subjects. Exploratory Aim 3: Examine whether slowing of startle latency, impaired P50 gating, and impaired cognition is predicted by KYN pathway activation, and whether it interacts with TOXO status.
Current treatments for schizophrenia are poorly effective in 20-30% of patients, thus making advances in this disorder of urgent concern. The finding of increased rates of infection with the parasite, Toxoplasma gondii (TOXO) in schizophrenia compared to the general population is an important clue to the cause of this disease for a subset of our patients. This project will study the mechanism by which TOXO may confer risk of schizophrenia, thus paving the way for the development of novel treatment targets for those schizophrenia patients with chronic TOXO infection.
|Wheeler, Marina G; Duncan, Erica; Davis, Michael (2017) Low startle magnitude may be a behavioral marker of vulnerability to cocaine addiction. Synapse 71:46-50|