Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2′,3′-cyclic nucleotide 3′-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 strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species 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, diffusion 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.

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Oligodendrocytes make myelin for rapid impulse propagation and contribute to the long-term survival of myelinated axons. The mechanisms by which oligodendroglial dysfunction(s) contribute to slowly progressive neurodegeneration are not well understood. Here, we demonstrate in Cnp1 mutant mice that secondary axonal degeneration in the subcortical white matter is associated with an age-dependent activation of both, innate and adaptive immune responses, including an expansion of infiltrating CD8+ T cells. While the detrimental role of lymphocytes in inherited myelin diseases is known, the role of activated microglia for the hypothetical cycle of inflammation/degeneration is unclear. We used a mild standardized cryolesion of the right parietal cortex to activate microglia at the vulnerable age of mouse puberty (postnatal day (P) 28). When applied to Cnp1 mutant mice, analyzed more than 3 months later, minor brain injury had acted as a "second hit" and significantly enhanced astrogliosis, microgliosis and axon degeneration, but not T cell infiltration. Interestingly, exacerbated neuropathological changes were also reflected by specific deterioration of working memory on top of an essentially normal basic behavior. We propose a model in which oligodendroglial dysfunctions can trigger a vicious cycle of neurodegeneration and low-grade inflammation that is amplified by nonspecific activators of the innate immune system. This interaction of genetic and environmental factors may be relevant for neuropsychiatric diseases associated with secondary neuroinflammation.

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