Brain white matter alterations in psychiatric diseases

Schizophrenia, which affects 1% of the general population, is characterized by distorted sense of reality, i.e. hallucinations and imaginary voices, absence of emotion, and erratic behavior and speech. While Schizophrenia has long been considered a disorder of brain connectivity, multiple lines of evidence have emerged that also point to white matter abnormalities in disease etiology. Hence, we focus on the question whether alterations in oligodendrocyte-expressed genes, such as CNP (2’,3’-cyclic nucleotide 3’-phosphodiesterase), and myelin can underlie defects that are causative of Schizophrenia or other neuropsychiatric diseases.

The impact of CNP partial loss-of-function genotypes in mouse and man
CNP accounts for ~4% of total myelin protein and is localized to non-compact regions of myelin, such as the inner mesaxon, paranodal loops and Schmidt-Lanterman incisures. Among all oligodendrocyte-associated genes, CNP is most robustly reduced at the mRNA and protein level in post-mortem brains of schizophrenic, bipolar, and major depressive patients. This suggests that reduced CNP expression is closely linked to disease process but not restricted to a single diagnostic category. Several genetic association studies have explored the potential impact of genetic variability in the CNP gene (chr17q21.2, 11kb) on the overall risk for schizophrenia with inconclusive results so far. Interestingly, a synonymous single nucleotide polymorphism (CNP SNP rs20070106) (Gly/Gly) in the CNP gene was found to influence CNP mRNA levels in the human cortex, with the less frequent 'A allele' resulting in a partial loss-of-function, i.e. lower steady state expression levels when compared to the 'G allele'. To address the pathophysiological relevance of reduced CNP expression, we compare partial loss-of-function genotypes in mouse and man. We analyze Cnp haploinsufficient mice and schizophrenic patients with the AA vs. GG genotype in SNP rs2070106 (in close collaboration with the ‘Devision of Clinial Neuroscience’, H. Ehrenreich), exploiting the GRAS (Goettingen Research Association for Schizophrenia) database.

In close collaboration with
Hannelore Ehrenreich, Göttingen
Jens Frahm/Susann Boretius, Göttingen