Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments
George Bartzokis1,2,3,4
1
Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, 2Laboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, 3The Brain Research Institute, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095,
4
Greater Los Angeles VA Healthcare System, West Los Angeles, CA, 90073
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction to Neuroglialpharmacology
- 2.1. Genetics of myelination
- 3. The Brain "Internet" Depends on the Speed and Synchrony Provided by Myelin
- 3.1. The myelin model of the human brain
- 3.2. Functional networks depend on synchrony and timing of oscillations
- 3.3. Intracortical myelin optimizes network oscillations and brain function
- 3.3.1. Measuring intracortical myelin (ICM) in vivo with MRI
- 3.4. Neurotransmitters can trigger oscillations and may also refine intracortical myelination
- 4. Distinctive Attributes of Oligodendrocytes and Their Myelin
- 4.1. High metabolic requirements
- 4.2. High cholesterol content and requirements
- 4.3. High iron content and requirements
- 4.4. Continued development and proliferation throughout the lifespan
- 4.5. Developmentally-determined heterogeneity and vulnerability continuum
- 4.6. Epigenetic modifications of oligodendrocytes throughout the lifespan
- 5. Essential Lipids: Omega 3 and 6 Fatty Acids (O3FA and O6FA) and their Metabolites
- 6. Psychiatric Epidemiology: Crossroads of Genes, Lipid Metabolism, and Nutrition
- 7. Myelotoxicity and Treatment Effects
- 8. Dysregulated Myelination in Schizophrenia (SZ) and Bipolar Disorder (BD)
- 9. Psychotropic Medications Influence Glia and Myelination: A Key Mechanism of Action?
- 9.1. Synaptic and non-synaptic neurotransmitter effects on glia
- 9.2. The cholinergic system and myelination
- 9.3. The dopaminergic system and myelination
- 10. Conclusions on Neuroglialpharmacology
- 11. Acknowledgement
- 12. References
1. ABSTRACT
Psychotropic treatments such as second generation or "atypical" antipsychotics are efficacious in a wide spectrum of psychiatric disorders ranging from schizophrenia to depression, bipolar disorder, and autism. These treatments are associated with peripheral metabolic derangements that are often also present in drug-naïve patients. Furthermore, altering lipid composition/levels (with omega 3 fatty acids) and ameliorating oxidative toxicities may treat/prevent disease. The above observations are reexamined from the perspective of a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination required higher metabolic resources that caused evolutionary adaptations resulting in our quadratic (inverted U) myelination trajectory that peaks in the sixth decade of life. It further proposes that optimal brain function depends on exquisite action potential synchronization that myelin makes possible and that myelin's exceptional vulnerability to subtle metabolic/oxidative abnormalities may promote both developmental and degenerative diseases. Available data are integrated herein to suggest that widely used psychotropic treatments have under-appreciated CNS metabolic and neurotransmitter effects on myelination, its plasticity, and repair that may substantially contribute to their mechanisms of action.
