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 language | English (US) |
|---|---|
| Pages (from-to) | 734-745 |
| Number of pages | 12 |
| Journal | Journal of Clinical Investigation |
| Volume | 128 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2018 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
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
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
VL - 128
SP - 734
EP - 745
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 2
ER -