Microglia ablation alleviates myelin-associated catatonic signs in mice
Hana Janova, … , Hannelore Ehrenreich, Klaus-Armin Nave
Hana Janova, … , Hannelore Ehrenreich, Klaus-Armin Nave
Published December 18, 2017
Citation Information: J Clin Invest. 2018;128(2):734-745. https://doi.org/10.1172/JCI97032.
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Research Article Inflammation Neuroscience

Microglia ablation alleviates myelin-associated catatonic signs in mice

Abstract

The underlying cellular mechanisms of catatonia, an executive “psychomotor” syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities.

Authors

Hana Janova, Sahab Arinrad, Evan Balmuth, Marina Mitjans, Johannes Hertel, Mohamad Habes, Robert A. Bittner, Hong Pan, Sandra Goebbels, Martin Begemann, Ulrike C. Gerwig, Sönke Langner, Hauke B. Werner, Sarah Kittel-Schneider, Georg Homuth, Christos Davatzikos, Henry Völzke, Brian L. West, Andreas Reif, Hans Jörgen Grabe, Susann Boretius, Hannelore Ehrenreich, Klaus-Armin Nave

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Figure 5

Catatonia and white matter inflammation in Cnp mutant mice and their treatment by CSF1R inhibition: Part II.

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Catatonia and white matter inflammation in Cnp mutant mice and their tre...
(A) APP+ swellings (indicating APP+ spheroids; no./mm2; 3 sections/brain) and (B) densitometric analysis of GFAP+ area (%; indicating astrogliosis; 1 section/brain). (C) CD3+ cells (no./mm2; indicating T lymphocyte invasion; 1 section/brain). (D and E) Representative IHC images illustrating CD3 and PDGFRα staining. (F) PDGFRα+ cells (no./mm2; indicating oligodendrocyte precursors; 1 section/brain). (G) Catatonic signs in WT, Cnp–/– (age of onset at 8 weeks of age, shown in Figure 2A), and Cnp+/– mice compared with mice with mutations in other myelin-related genes (Mbp+/–, Plp–/y). Age of onset of catatonia in heterozygous mice (Cnp+/–, Mbp+/–) seen at around 60–72 weeks and in Plp–/y mice at 25 weeks. All data in A, B, C, F, and G were individually tested for Gaussian distribution using the Kolmogorov-Smirnov test. Nonparametric Kruskal-Wallis test was performed for B, C, and G for multiple group comparisons, followed by post hoc 1-tailed Mann-Whitney U test. Two-way ANOVA was performed for A and F, followed by post hoc 1-tailed unpaired t test. All data are shown as mean ± SEM; n indicated within bars.