BBB Seminar: Bjarte Håvik
The effect of synaptic activity-regulated genes on the risk of schizophrenia
Department of Clinical Medicine, Section of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen
Schizophrenia is a serious psychotic disorder with unknown etiology and a high incidence of heritability. A recent population-wide study using the Swedish national health register estimated that 64% of the disease risk could be attributed to inheritance. Nevertheless, there has been a remarkable lack of replicated genetic susceptibility factors, and there is a need to identify genes and signaling pathways that significantly contribute to disease risk.
Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. To discover new genetic risk factors we have therefore performed unbiased microarray-based screens for genes that are implicated in synaptic plasticity (high-frequency stimulation-induced long-term potentiation (HFS-LTP) and brain-derived neurotrophic factor-induced LTP (BDNF-LTP)). Long-term potentiation of synaptic strength in the rat hippocampus, which is a model that reflects mechanisms of learning and memory, was unexpectedly linked to the induction of immunity-related pathways, including complement activation and antigen-presentation (MHC class I and class II). This finding was unexpected as the brain traditionally is considered to be immunity deprived.
Subsequent genetic association studies in schizophrenia case-control samples revealed genome-wide statistical significant associations to specific regulators of the classical complement cascade. Furthermore, immunity-related genes as well as other LTP-regulated factors associated to specific cognitive traits in healthy individuals.
The strongest effect on risk of schizophrenia was observed for two regulators of the classical complement cascade, CSMD1 and CSMD2. We have generated knock-out mice for both genes. Preliminary data illustrate a dynamic expression pattern of these proteins in the postnatal developing brain, and mice lacking CSMD1 show altered behavior linked to anxiety and depression. In summary, our data suggest that molecules of the innate immune system unexpectedly are expressed in neurons and that they can modulate the functioning of the brain in both health and disease.
Host: Boleslaw Srebro, Department of Biomedicine