Micro(glial)-managing executive function: white matter inflammation drives catatonia

White matter abnormalities are prevalent in neuropsychiatric disorders such as schizophrenia, but it is unclear whether these abnormalities represent a cause or consequence of these disorders. Reduced levels of the myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (CNP) are associated with the schizophrenic symptom catatonia in both humans and mouse models. In this issue of the JCI, Janova et al. show that reduced CNP levels correlate with catatonia and white matter inflammation in human subjects. Furthermore, they demonstrate that microglial ablation prevents and alleviates catatonic signs in Cnp^–/– mice, indicating that microglial-mediated inflammation causes catatonia. Together, this study identifies a cellular mechanism by which subtle myelin abnormalities cause low-grade neuroinflammation and catatonic behavior.

As reduced levels of CNP are associated with catatonic behavior and neuroinflammation in both mice and humans, Janova et al. asked whether microglial-mediated white matter inflammation underlies catatonia in human subjects and mouse models (14). Using two independent data sets of schizophrenic human subjects, Janova et al. found that schizophrenic subjects have a high prevalence of catatonic signs and show increased symptom severity with age. Presence of the CNP loss-of-function SNP rs2070106-AA correlated with increased severity of catatonic signs in schizophrenic patients. Furthermore, MRI scans of rs2070106-AA carriers in the general population showed an age-dependent increase in frontotemporal white matter hyperintensities, suggestive of neuroinflammation in these regions. Together, these findings indicate that reduced CNP levels are associated with white matter tract inflammation and catatonic signs in humans.

Janova and colleagues next turned to a mouse model to investigate the underlying cellular mechanism of this myelin-associated catatonia (14). Young Cnp^–/– mice exhibited catatonic behavior in the absence of any gross motor deficits and had signs of both microglial activation and axon transport defects. The authors further investigated whether microglial-mediated neuroinflammation causes catatonia in these mice by pharmacologically inhibiting colony-stimulating factor 1 receptor (CSF1R), which results in microglial depletion (15, 16). Excitingly, pretreatment of Cnp^–/– mice with the CSF1R inhibitor PLX5622 prior to onset of catatonic behavior prevented development of this symptom (Figure 1). PLX5622 treatment also reduced microgliosis and axon transport defects, with these effects persisting up to 4 weeks after administration. This finding demonstrates a long-lasting antiinflammatory effect of microglial ablation. Janova and colleagues also used magnetic resonance spectroscopy to evaluate levels of the metabolite myo-inositol, a putative indicator of local neuroinflammation and microglial activation. Myo-inositol levels were elevated in white matter of Cnp^–/– mice and further increased with age. Prophylactic microglial ablation was also sufficient to prevent elevated myo-inositol levels in Cnp^–/– mice, suggesting that microglial depletion prevents the progressive neuroinflammatory phenotype of these mice.

Figure 1

Microglial-mediated inflammation triggered by myelin deficits causes catatonic behavior. (A) In this issue, Janova et al. show that a minor myelin abnormality in mice lacking CNP causes microglial-mediated neuroinflammation and leads to catatonic symptoms. (B) Microglia ablation by the CSF1R inhibitor PLX5622 can both prevent and treat neuroinflammation and catatonia.

Importantly, microglial ablation was also sufficient to alleviate catatonic behavior in aging Cnp^–/– mice already in an advanced state of neuroinflammation and neurodegeneration. Treatment of Cnp^–/– mice with PLX5622 at 6 months of age also reduced microglial activation, axonal transport deficits, and astrocytosis in white matter. Finally, Janova et al. found that catatonic signs are a general phenotype of mice with mild myelin abnormalities and low-grade neuroinflammation, as these symptoms were also observed in mice heterozygous for Mbp and mice lacking myelin proteolipid protein (Plp^–/y).

By combining human data and mechanistic insight from the mouse, Janova and colleagues have described a cellular mechanism by which subtle myelin abnormalities lead to microglial-mediated inflammation and catatonic behavior (Figure 1). This study represents a notable advance, as it bridges the gap between correlation and causation for myelin impairment in a complex neuropsychiatric symptom. In addition, Janova et al. have identified microglia as a promising cellular target for prevention and treatment of catatonia (14). However, it is important to note the potential effect of CSF1R inhibitors on nonmicroglial cells as a caveat to consider for this and future studies (17).

While Janova et al. (14) identify myelin-associated microgliosis as a cause of catatonic behavior, questions remain about how the observed pathological events fit together. What exactly is the putative myelin defect resulting from a CNP (or MBP or PLP) deficit that activates microglia, and how does such a defect result in microglia activation? Does the myelin defect directly trigger microglial inflammation, or does it do so indirectly, such as by inducing neurodegeneration? Janova et al. found that microglial ablation in Cnp^–/– mice only partially prevented or ameliorated signs of neurodegeneration, suggesting that neurodegeneration may be at least partially independent of microglial activation (14). In addition, while Cnp^–/–, Cnp^+/–, and Plp^–/y mice develop neurodegenerative symptoms, Mbp^+/– mice do not (13), yet all of these mice develop catatonia. Impaired axonal health may therefore not be the trigger for microglial activation, as was previously hypothesized (11). However, it is possible that Mbp^+/– and other myelin-mutant mice develop subtle myelin-dependent changes in axonal function that cause microgliosis. Alternatively, the defect in myelin itself may directly trigger microglial activation. It will be important to determine whether microglial ablation can similarly prevent and treat catatonic symptoms in mice with other minor myelin deficits, such as those observed in Mbp^+/– and Plp^–/y mice, and to use the commonalities between these models to identify the missing link between myelin and neuroinflammation.

The downstream mechanism by which neuroinflammation leads to catatonic behavior is also still unclear. Janova et al. speculate that white matter neuroinflammation may eventually impair synaptic circuit function (14). This could occur through multiple microglial-driven mechanisms, such as through release of neurotoxic ROS (18) or aberrant reactivation of complement cascade–mediated synaptic pruning (19–22). Notably, increased expression of the complement cascade component C4 has been correlated with schizophrenia in humans (22). Alternatively, signs of increased blood-brain barrier (BBB) permeability have also been correlated with schizophrenic symptoms (23). It will therefore also be important to investigate whether myelin-associated neuroinflammation compromises BBB integrity.

Interestingly, the Cnp^+/– mouse exhibits behavioral abnormalities present in many neuropsychiatric diseases, including enhanced anxiety, depression, and impaired social and exploratory behavior (10). As white matter changes are associated with a wide range of disorders that affect higher-order processing, including schizophrenia, bipolar disorder, depression, autism, Huntington’s disease, and Alzheimer’s disease (2–4), future studies should investigate whether this myelin-associated neuroinflammation mechanism is generalizable to other symptoms of neuropsychiatric diseases. The findings by Janova et al. indicate a causal link between myelin deficits and catatonic behavior, suggesting that further investigation into this cellular mechanism could have far-reaching implications for the study and treatment of neurological diseases.

This work was supported by the NIH/National Institute of Neurological Disorders and Stroke (R01NS062796, R01NS097428, R01NS095889), the National Multiple Sclerosis Society (RG5203A4), and the Rachleff Family Endowment. We thank members of the Chan laboratory for insightful and helpful discussions and Lindsay Osso for her help with illustration of the figure.

Address correspondence to: Sarah E. Pease-Raissi, University of California, San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, Room 260, Box 3206, San Francisco, California 94158, USA. Phone: 415.353.4390; Email: sarah.raissi@ucsf.edu.

Conflict of interest: J.R. Chan is cofounder of Inception 5 and a consultant for Inception Sciences. S.E. Pease-Raissi and J.R. Chan declare research support from Mead Johnson Nutrition.

Reference information: J Clin Invest. 2018;128(2):564–566. https://doi.org/10.1172/JCI98761.

See the related article at Microglia ablation alleviates myelin-associated catatonic signs in mice.

1. Philips T, Rothstein JD. Oligodendroglia: metabolic supporters of neurons. J Clin Invest. 2017;127(9):3271–3280.
   View this article via: JCI PubMed CrossRef Google Scholar
2. Nave KA, Ehrenreich H. Myelination and oligodendrocyte functions in psychiatric diseases. JAMA Psychiatry. 2014;71(5):582–584.
   View this article via: PubMed CrossRef Google Scholar
3. Filley CM, Fields RD. White matter and cognition: making the connection. J Neurophysiol. 2016;116(5):2093–2104.
   View this article via: PubMed CrossRef Google Scholar
4. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7):361–370.
   View this article via: PubMed CrossRef Google Scholar
5. Hakak Y, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci U S A. 2001;98(8):4746–4751.
   View this article via: PubMed CrossRef Google Scholar
6. Tkachev D, et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet. 2003;362(9386):798–805.
   View this article via: PubMed CrossRef Google Scholar
7. Mitkus SN, et al. Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophr Res. 2008;98(1–3):129–138.
   View this article via: PubMed Google Scholar
8. Peirce TR, et al. Convergent evidence for 2′,3′-cyclic nucleotide 3′-phosphodiesterase as a possible susceptibility gene for schizophrenia. Arch Gen Psychiatry. 2006;63(1):18–24.
   View this article via: PubMed CrossRef Google Scholar
9. Iwamoto K, Ueda J, Bundo M, Nakano Y, Kato T. Effect of a functional single nucleotide polymorphism in the 2′,3′-cyclic nucleotide 3′-phosphodiesterase gene on the expression of oligodendrocyte-related genes in schizophrenia. Psychiatry Clin Neurosci. 2008;62(1):103–108.
   View this article via: PubMed CrossRef Google Scholar
10. Hagemeyer N, et al. A myelin gene causative of a catatonia-depression syndrome upon aging. EMBO Mol Med. 2012;4(6):528–539.
    View this article via: PubMed CrossRef Google Scholar
11. Lappe-Siefke C, et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet. 2003;33(3):366–374.
    View this article via: PubMed CrossRef Google Scholar
12. Wieser GL, et al. Neuroinflammation in white matter tracts of Cnp1 mutant mice amplified by a minor brain injury. Glia. 2013;61(6):869–880.
    View this article via: PubMed CrossRef Google Scholar
13. Poggi G, et al. Cortical network dysfunction caused by a subtle defect of myelination. Glia. 2016;64(11):2025–2040.
    View this article via: PubMed CrossRef Google Scholar
14. Janova H, et al. Microglia ablation alleviates myelin-associated catatonic signs in mice. J Clin Invest. 2018;128(2):734–745.
    View this article via: JCI PubMed Google Scholar
15. Waisman A, Ginhoux F, Greter M, Bruttger J. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 2015;36(10):625–636.
    View this article via: PubMed CrossRef Google Scholar
16. Dagher NN, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation. 2015;12:139.
    View this article via: PubMed Google Scholar
17. Chitu V, Gokhan Ş, Nandi S, Mehler MF, Stanley ER. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends Neurosci. 2016;39(6):378–393.
    View this article via: PubMed CrossRef Google Scholar
18. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.
    View this article via: PubMed CrossRef Google Scholar
19. Stevens B, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–1178.
    View this article via: PubMed CrossRef Google Scholar
20. Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016;36:128–134.
    View this article via: PubMed CrossRef Google Scholar
21. Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–389.
    View this article via: PubMed CrossRef Google Scholar
22. Sekar A, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530(7589):177–183.
    View this article via: PubMed CrossRef Google Scholar
23. Schoknecht K, Shalev H. Blood-brain barrier dysfunction in brain diseases: clinical experience. Epilepsia. 2012;53(suppl 6):7–13.
    View this article via: PubMed Google Scholar