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Anxiety; axonal degeneration; diffusion tensor imaging; low-grade
inflammation; social withdrawal
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.
