Schizophrenia & Bipolar Disorder

Schizophrenia and bipolar disorder (BP), also known as manic-depressive disorder, are distinct psychiatric disorders hat share some common symptoms and a partially overlapping genetic aetiology. Schizophrenia is characterized by positive symptoms, such as hallucinations and delusions, and negative symptoms, like impaired cognition and emotion. Patients with BP have episodes of mania, including increased physical and mental activity with elevated mood and exaggerated optimism, mixed or followed by episodes of depression, with lost of interest in usual activities, fatigue, worry, anxiety, and thoughts of death or suicide. Together, these disorders affect approximately 2 % of the population. Their heritability has been estimated to be around 50 % for schizophrenia and 80% for BP. Both disorders share around 25% of the susceptible genes.

In the last years, a number of these susceptibility genes have been identified in linkage and association studies, including genome-wide association studies. However, the functions of many of the associated genes or gene loci are completely unknown and, thus, the human genetic findings do not readily translate into a better understanding of the disease pathologies. This gap can only be closed with appropriate animal models, because they allow the use of research methods that cannot be used in humans. Consequently, we are developing animal models for schizophrenia and bipolar disorder that are based on human genetic studies.

For example, we have recently described a transgenic mouse strain carrying the human G72/G30 gene locus. This locus has originated late during human evolution and is only present in anthropoid primates. The major protein encoded in this locus, LG72, has no readily identifiable structural domains, thus making it difficult to assign a function. Studies performed in vitro, however, suggest that LG72 may modulate the enzymatic activity of d-amino acid oxidase or influence mitochondrial functions. G72/G30 transgenic mice express LG72 throughout the brain and display a number of behavioral phenotypes that are relevant to schizophrenia. They have deficits in sensorimotor gating (Figure 1), which could be reversed with haloperidol, increased sensitivity to PCP, motor-coordination deficits, increased compulsive behaviors and deficits in smell identification.

We are currently in the process of analyzing the molecular mechanisms leading to these behavioral changes.

This project is supported by the Bundesministerium für Bildung und Forschung (NGFN MOODS).