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Abstract

Severe mental illnesses have been linked to white matter abnormalities, docu- mented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase) is among the oligodendrocyte/myelin-associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional ‘pro-inflammatory hit’. This phenotype is strik- ingly similar in Cnp heterozygous mice and patients with mental disease carrying the AAgenotypeat CNP SNPrs2070106.The characteristicfeatures inbothspecies with their partial CNP ‘loss-of-function’ genotype are best described as ‘catatonia- depression’ syndrome. As a consequence of perturbed CNP expression, mice show secondary low-grade inflammation/neurodegeneration. Analogously, in man, dif- fusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases.