TY - JOUR
T1 - Microglia ablation alleviates myelin-associated catatonic signs in mice
AU - Janova, Hana
AU - Arinrad, Sahab
AU - Balmuth, Evan
AU - Mitjans, Marina
AU - Hertel, Johannes
AU - Habes, Mohamad
AU - Bittner, Robert A.
AU - Pan, Hong
AU - Goebbels, Sandra
AU - Begemann, Martin
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
N1 - Funding Information:
This work was supported by the Max Planck Society, the Max Planck Förderstiftung, the Deutsche Forschungsgemeinschaft (DFG) (CNMPB and SPP1757), EXTRABRAIN EU- FP7, and the Niedersachsen-Research Network on Neuroinfectiology (N- RENNT). SHIP is part of the Community Medicine Research Net of the University Medicine Greifswald, which is funded by the Federal State of Mecklenburg–West Pomerania. Genome-wide data in SHIP have been supported by a joint grant from Siemens Healthineers, Erlangen, and the Federal State of Mecklenburg–West Pomerania. KAN holds a European Research Council Advanced Investigator grant. The authors thank all subjects for participating in the study, and all colleagues who have contributed over the past decade to GRAS data collection.
Funding Information:
This work was supported by the Max Planck Society, the Max Planck Förderstiftung, the Deutsche Forschungsgemeinschaft (DFG) (CNMPB and SPP1757), EXTRABRAIN EU-FP7, and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT). SHIP is part of the Community Medicine Research Net of the University Medicine Greifswald, which is funded by the Federal State of Mecklenburg–West Pomerania. Genome-wide data in SHIP have been supported by a joint grant from Siemens Healthineers, Erlangen, and the Federal State of Mecklenburg– West Pomerania. KAN holds a European Research Council Advanced Investigator grant. The authors thank all subjects for participating in the study, and all colleagues who have contributed over the past decade to GRAS data collection.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI97032
DO - 10.1172/JCI97032
M3 - Article
C2 - 29252214
AN - SCOPUS:85041479338
SN - 0021-9738
VL - 128
SP - 734
EP - 745
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -