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Schizophrenia is a major psychiatric illness that occurs in approximately 0.5% of all individuals. This disease is characterized by the presence of different classes of symptoms. Firstly, there are positive symptoms such as delusions and hallucinations. Secondly, there are negative symptoms such as social isolation, blunted emotions, poverty of speech and anhedonia – the inability to experience pleasure from normally pleasurable life events. Lastly, there are impairments in various cognitive domains affecting short-term planning and working memory.Different genes that play an important role in brain development and functioning have been implied in schizophrenia. The presence of these faulty gene variants gives rise to subtle dysfunctions in multiple brain circuits. Firstly, there is a hyperactivity of the mesolimbic tract that connects the brain stem with the striatum and uses the neurotransmitter dopamine. This hyperactivity is held responsible for the positive symptoms. Secondly, there is a dysregulation of internal circuits in the cerebral cortex and the hippocampus that use the neurotransmitters glutamate and GABA. The malfunctioning of these circuits is assumed to be directly responsible for the negative and the cognitive symptoms. The existing drugs against schizophrenia – the antipsychotics – work primarily by blocking the activity of the mesolimbic tract. Therefore, they are only effective in alleviating the positive symptoms. A better understanding of the mechanisms leading to schizophrenia is a prerequisite for the rational development of more effective medication. One of the crucial steps in the fundamental research of diseases is the development of animal models. For psychiatric diseases, this is a daunting task since it is hard to model the typically human symptoms of those diseases in animals Yet, in the case of schizophrenia, a number of behavioural tests exist that can diagnose abnormalities in animals that mimic the different classes of schizophrenia symptoms. If these behavioural abnormalities are present, those animal models can be used to study in detail the brain circuits that have been implied in schizophrenia.In the broader framework of our research into the function of g-Secretase, a protein complex that cleaves other proteins and in that way regulates their function, we created a knockout mouse that lacks a specific variant of this complex, the Aph1B/C-g-Secretase (Aph1BC-/- mice). These mice perform poorly on the specific behavioural tests that are used to model the positive and cognitive symptoms of schizophrenia. Furthermore, the administration of antipsychotics can correct the impairment in one of the assays that measures the positive symptoms There are also different lines of evidence for abnormalities in the two major brain circuits implied in schizophrenia. Interestingly, the Aph1B/C variant of the g-Secretase complex is present in high levels in the circuit where the primary deficit in schizophrenia is thought to be.Neuregulin-1 (Nrg1) is one of the proteins that are cleaved by g-Secretase. The gene that encodes this protein has convincingly been linked to an increased risk of schizophrenia. Here, it is shown that the cleavage of Nrg1 is disturbed in the brain of the Aph1BC-/- mice. Further, one of the Nrg1 variants that increase the risk of schizophrenia is less susceptible to cleavage by Aph1B/C-g-Secretase than wild-type Nrg1. In light of these results, it is worthwhile to further investigate the potential of g-Secretase stimulation as a therapeutic strategy against schizophrenia and related neuropsychiatric diseases. To validate this strategy, it should first be established that phenotypes we have observed in Aph1BC-/- mice are acute, and not developmental, in nature. Subsequently, one could think about the development of small molecule drugs that increase g-Secretase expression or activi

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