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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

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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 1

Age–dependent association of the loss-of-function genotype CNP rs2070106-AA with catatonia in 2 independent schizophrenia cohorts and with WMH in a general population sample.

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Age–dependent association of the loss-of-function genotype CNP rs2070106...
(A) Bars show mean age of schizophrenic subjects (GRAS), sorted by severity of catatonic signs. Red line denotes percentage of risk for genotype carriers (rs2070106-AA) within each severity group. Note that severity of catatonic signs increases with age. Two-sided values for Kruskal-Wallis (P = 7.6 × 10–9) and Jonckheere-Terpstra (P = 1.3 × 10–9).Mean ± SEM. Also note that CNP rs2070106-AA carriers are most frequent (18.2%) among individuals with highest expression of catatonic signs compared with noncatatonic subjects (10.4%). Two-sided P value for Mann-Whitney U test for extreme-group comparison given in the figure. (B) Distribution of CNP rs2070106 genotype in the Würzburg replication sample of schizophrenia patients based on dichotomous catatonia classification. The AA genotype is significantly more prevalent in patients with (17.9%) than without catatonia (7.8%). Two-sided P values from χ2 test given. (C) Left panel: interaction effect between age and genotype in SHIP-TREND-0 sample on overall WMH volume (minimum 10 mm3 per single WMH cluster). Shown are WMH volume residuals after correcting for intracranial volume, age (nonlinear), and gender. Genotype and age-genotype interaction term contributed 1.1% of variance to overall WMH volumes. Right panel: frequency map averaging all subjects of the general population (SHIP-TREND-0; n = 552), analyzed here. Data highlight WMH appearance predominantly in frontal regions.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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