Myelination, oligodendrocytes, and serious mental illness

Abstract

Historically, the human brain has been conceptually segregated from the periphery and further dichotomized into gray matter (GM) and white matter (WM) based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. These simplistic dichotomies were unfortunately extended to conceptually segregate neurons from glia, cognition from behavior, and have been codified in the separation of clinical and scientific fields into medicine, psychiatry, neurology, pathology, etc. The discrete classifications have helped obscure the importance of continual dynamic communication between all brain cell types (neurons, astrocytes, microglia, oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery through multiple signaling systems. The signaling systems range from neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation, and myelination processes and orchestrate the development, plasticity, maintenance, and repair that continually optimize function of neural networks. A more comprehensive, evolution-based, systems biology approach that integrates brain, body, and environmental interactions may ultimately prove more fruitful in elucidating the complexities of human brain function. The historic focus on neurons/GM is rebalanced herein by highlighting the importance of a systems-level understanding of the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating neuropsychiatric diseases. Herein we highlight the role of glia, especially the most recently evolved oligodendrocytes and the myelin they produce, in achieving and maintaining optimal brain function. The human brain undergoes exceptionally protracted and pervasive myelination (even throughout its GM) and can thus achieve and maintain the rapid conduction and synchronous timing of neural networks on which optimal function depends. The continuum of increasing myelin vulnerability resulting from the human brain's protracted myelination underlies underappreciated communalities between different disease phenotypes ranging from developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities also expose significant yet underexplored opportunities for novel treatment and prevention approaches that have the potential to considerably reduce the tremendous burden of neuropsychiatric disease.

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

“…Whether age-dependent changes in testosterone are a contributing factor to age-related white matter abnormalities (48) or the reduced regenerative capacity of myelin (49) remains to be explored. Importantly, the influence of androgens on the plasticity and regeneration of myelin may not only have consequences for demyelinating diseases, because recent studies have linked myelin abnormalities to a wide range of psychiatric disorders and cognitive aging (50,51).…”

Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders

“…The effects of prenatal immune activation on myelinrelated dysfunctions are particularly interesting in light of the potential role of myelination and white matter abnormalities present in schizophrenia and other neurodevelopmental disorders (Haroutunian et al 2014;Mighdoll et al 2015;ChavarriaSiles et al 2016). Indeed, myelin provides the basis for rapid impulse conduction in the central nervous system and acts as electrical insulation for the unsheathed axon, which both helps to preserve the amplitude and increase the conduction velocity of the propagating axonal potential (Nave and Werner 2014;Normand and Rasband 2015).…”

Age-related microstructural differences quantified using myelin water imaging and advanced diffusion MRI

“…In contrast to nonhuman primates, these maturating and regressive processes occur heterochronically in different brain regions (Haroutunian et al, 2014).…”