Microglia ablation alleviates myelin-associated catatonic signs in mice

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 & 3 others Susann Boretius, Hannelore Ehrenreich, Klaus Armin Nave

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)734-745
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number2
DOIs
StatePublished - Feb 1 2018

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Microglia
Myelin Sheath
Catatonia
Schizophrenia
Inflammation
Myelin Proteins
Executive Function
Oligodendroglia
Psychiatry
Phosphotransferases
Biomarkers
Alleles
Population
Genes
White Matter
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Janova, H., Arinrad, S., Balmuth, E., Mitjans, M., Hertel, J., Habes, M., ... Nave, K. A. (2018). Microglia ablation alleviates myelin-associated catatonic signs in mice. Journal of Clinical Investigation, 128(2), 734-745. https://doi.org/10.1172/JCI97032

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

In: Journal of Clinical Investigation, Vol. 128, No. 2, 01.02.2018, p. 734-745.

Research output: Contribution to journalArticle

Janova, H, Arinrad, S, Balmuth, E, Mitjans, M, Hertel, J, Habes, M, Bittner, RA, Pan, H, Goebbels, S, Begemann, M, Gerwig, UC, Langner, S, Werner, HB, Kittel-Schneider, S, Homuth, G, Davatzikos, C, Völzke, H, West, BL, Reif, A, Grabe, HJ, Boretius, S, Ehrenreich, H & Nave, KA 2018, 'Microglia ablation alleviates myelin-associated catatonic signs in mice', Journal of Clinical Investigation, vol. 128, no. 2, pp. 734-745. https://doi.org/10.1172/JCI97032
Janova H, Arinrad S, Balmuth E, Mitjans M, Hertel J, Habes M et al. Microglia ablation alleviates myelin-associated catatonic signs in mice. Journal of Clinical Investigation. 2018 Feb 1;128(2):734-745. https://doi.org/10.1172/JCI97032
Janova, Hana ; Arinrad, Sahab ; Balmuth, Evan ; Mitjans, Marina ; Hertel, Johannes ; Habes, Mohamad ; Bittner, Robert A. ; Pan, Hong ; Goebbels, Sandra ; Begemann, Martin ; Gerwig, Ulrike C. ; Langner, Sönke ; Werner, Hauke B. ; Kittel-Schneider, Sarah ; Homuth, Georg ; Davatzikos, Christos ; Völzke, Henry ; West, Brian L. ; Reif, Andreas ; Grabe, Hans Jörgen ; Boretius, Susann ; Ehrenreich, Hannelore ; Nave, Klaus Armin. / Microglia ablation alleviates myelin-associated catatonic signs in mice. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 2. pp. 734-745.
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AU - Arinrad, Sahab

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AU - Hertel, Johannes

AU - Habes, Mohamad

AU - Bittner, Robert A.

AU - Pan, Hong

AU - Goebbels, Sandra

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AU - Gerwig, Ulrike C.

AU - Langner, Sönke

AU - Werner, Hauke B.

AU - Kittel-Schneider, Sarah

AU - Homuth, Georg

AU - Davatzikos, Christos

AU - Völzke, Henry

AU - West, Brian L.

AU - Reif, Andreas

AU - Grabe, Hans Jörgen

AU - Boretius, Susann

AU - Ehrenreich, Hannelore

AU - Nave, Klaus Armin

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