The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.

The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia.

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

Toxoplasma gondii-A Gastrointestinal Pathogen Associated with Human Brain Diseases.

Serious psychiatric disorders such as schizophrenia, bipolar disorder, and major depression are important causes of mortality and morbidity worldwide. While these are primarily diseases involving altered brain functioning, numerous studies have documented increased rates of gastrointestinal inflammation and dysfunction in many individuals with these disorders. Toxoplasma gondii is an apicomplexan protozoan intracellular parasite with a widespread distribution in both developed and developing countries. Toxoplasma organisms enter the ecosystem through the shedding of oocysts by Toxoplasma-infected felines. In almost all cases of postnatal human infection, Toxoplasma enters its hosts through the intestinal tract either by the ingestion of oocysts or by the consumption of meat from food animals which themselves were infected by Toxoplasma oocysts. It had previously been thought that most cases of Toxoplasma infection in immune competent children and adults were inapparent and asymptomatic. However, recent studies cast doubt on this concept as exposure to Toxoplasma has been associated with a range of acute and chronic symptoms. Of particular note has been the finding of an increased rate of a range of neurological and psychiatric disorders associated with serological evidence of Toxoplasma exposure. A role of Toxoplasma infection in brain diseases is also supported by the consistent finding of altered cognition and behavior in animal models of infections. Much of the attention relating to the role of Toxoplasma infection in neuropsychiatric disorders has focused on the brain, where Toxoplasma tissue cysts can persist for extended periods of time. However, recent discoveries relating to the role of the gastrointestinal tract in cognition and behavior suggest that Toxoplasma may also increase susceptibility to human brain diseases through immune activation, particularly involving the gastrointestinal mucosa. The study of the pathways relating to the pathobiology and immunology of Toxoplasma infection may provide insights into the pathogenesis of a range of human neuropsychiatric disorders as well as into cognitive functioning in otherwise healthy individuals.

Novel alpha7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia.

Abnormal alpha7 nicotinic acetylcholine receptor activity contributes to sensory gating and cognitive deficits in schizophrenic individuals. Negligible differences in alpha7 mRNA levels between disease and control states have led to conclusions that cholinergic dysfunction in schizophrenia (SZ) must occur post-transcriptionally. Alternatively, we propose that the dysregulation of splice variants of the alpha7 receptor could account for cholinergic deficiencies observed in this disease. Here, we isolated multiple alpha7 splice variants including exon deletions and those associated with a novel 124-127 base insertion following exon 4. Transcripts containing this new exon originated from sense strand-oriented RNA (vs. antisense), and in silico translations produced putative subunits with unique amino termini. Quantitative real-time polymerase chain reaction analyses indicated that one novel isoform was significantly downregulated (P < or = 0.03) in post-mortem prefrontal cortex of individuals with SZ (n = 35) compared with controls (n = 34). Ten brain regions (cerebellum, thalamus, corpus callosum, caudate, putamen and five areas of the cortex) were further screened for alpha7 isoforms in three individuals of each group. Semiquantitative analyses showed that each alpha7 mRNA subtype was present in each brain region, but all were particularly deficient in the corpus callosum in schizophrenics vs. controls (P < or = 0.0002 to 0.05 for different isoforms). Our data demonstrate that alpha7 transcription is altered in several ways in SZ, suggesting that transcription-level mechanisms could account in part for the impaired cholinergic neurotransmission observed in this disease.

Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder.

Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanisms for these disease-associated cholinergic deficits are not known. In vitro, the protein RIC-3 (resistance to inhibitors of cholinesterase-3) aids the assembly and trafficking of alpha7-nAChRs but has unclear action on the biogenesis of alpha4/beta2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, alpha7-, alpha4- and beta2-nAChRs transcript levels in postmortem prefrontal cortex of individuals with SZ (n=31), BP (n=28) and unaffected controls (NC, n=33). Of the 28 individuals with BP, 20 had a history of psychotic symptoms. We compared relative message abundances between diagnostic groups and tested correlations of RIC-3 with each nAChR message subtype. RIC-3 and alpha4 messages were significantly increased in BP compared with NC (RIC-3, P< or =0.002; alpha4, P< or =0.04). RIC-3 message was also upregulated in SZ (P< or =0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P< or =0.02) and compared with NC (RIC-3, P< or =0.0003; alpha4, P< or =0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P< or =2.5e-05; alpha4, P< or =2.5e-09; beta2, P< or =0.003) and in SZ (alpha7, P< or =1e-07; alpha4, P< or =7e-07; beta2, P< or =3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P< or =0.003; alpha4, P< or =3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P< or =0.04), but showed no significant correlation in BP with psychoses (P< or =0.31) compared with a significant correlation in BP without psychoses (P< or =0.007). In conclusion, coordinated RIC-3/alpha4 upregulation and discordant RIC-3/beta2 levels suggest that alpha4/beta2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the beta2 nAChR subunit in a subset of patients affected by psychotic features.