Myelination and oligodendrocyte functions in psychiatric diseases.

The evolution of the human brain is marked not only by a major expansion of the neocortex but also by an enormous increase of the subcortical white matter. White matter tracts comprise the axonal output of some 1010 cortical projection neurons, which constitute a giant cellular network, recently referred to as the connectome. About half the human brain comprises myelinated axonal tracts that connect the cortex with subcortical structures and, most importantly, interconnect cortical areas with each other. Lesions affecting central nervous system white matter such as in stroke and demyelinating diseases typically cause acutemotor and sensory deficits, but white matter abnormalities also cause cognitive dysfunction, including the kinds of abnormalities seen in psychiatric conditions. Subcortical axons differ widely in caliber (0.1-3 μm), and transcallosal projections can reach 20 cm in length. Given the average size of cortical pyramidal neurons (15 μm), the axonal compartment occupies more than 99% of the neuronal cytoplasm and typically terminates in a distant, highly branched synaptic arbor. Thus, maintaining lifelong functional connections between neuronal somata and their presynaptic terminals constitutes a major cell biological challenge. This includes not only the rapid and reliable conduction of action potentials, which must be followed by repolarization of the axonal membrane, but also the continuous motordriven transport of mitochondria, organelles, and vesicles with a complex cargo of signaling proteins and enzymes critical for synaptic transmission. Obviously, maintaining these axonal functions is an energy-consuming process, and energy depletion in white matter tracts as illustrated dramatically by ischemic stroke often results in irreversible loss of connectivity, thereby disrupting brain function. Axons in the white matter associate closely with myelinforming oligodendrocytes. They physically enwrap and ensheath axons along their length, except for the nodes of Ranvierwhere action potentials are generated. During brain development,myelination proceeds in a posterior to anterior gradient after the neuronal circuitry has been laid down andpeaks in early postnatal life. It also involves axons within the cortical gray matter, where myelin synthesis continues even years after puberty, specifically in the prefrontal area. In the adult brain, myelin is more dynamic than previously thought, allowing for a substantial turnover with time.1 Other glial cells in white matter include astrocytes and the more recently identified NG2 cells, which also serve as oligodendrocyte progenitor cells. Astrocytes contribute to the formation of a blood-brain barrier and are gap junction coupled to oligodendrocytes and myelin. This suggests that their known function in neurovascular coupling is partly maintained in white matter. For the most part, oligodendrocytes provide both electrical insulation for rapid impulse propagation and trophic support for axons, which appear metabolically deprived by myelin itself. This support depends on noncompacted regions of myelin that connect the oligodendrocyte soma (via paranodal loops) to the periaxonal cytosolic space under the myelin sheath. This tubelike cytosolic compartment (myelinic channel) also runs parallel to the axon, facing the axonal internode along its length, facilitating metabolic exchange.2 Recent genetic evidence suggests that oligodendrocytes sustain axonal energy metabolism by performing aerobic glycolysis and delivering lactate to the myelinated compartment via monocarboxylate transporters.3 Interestingly, there is growing evidence that abnormal metabolic support by oligodendrocytes is involved in the motor neuron disorder amyotrophic lateral sclerosis. Such non–cell-autonomous functions of oligodendrocytes should be kept in mind when exploring their possible involvement in psychiatric diseases. Numerous clinical studies using imaging techniques have reportedwhitematter changes in schizophrenia, depression, autism, Alzheimer disease, andHuntington chorea. In all these studies, the key question is the relationship of cause and effect in a correlative finding.Moreover, long-termmedicationmayhave itsowneffecton brain atrophy that is difficult to control.4 But, why should oligodendrocytes be causally involved in any of these disorders? Neuronal loss in chronic brain diseases certainly leads to axon loss and will invariably cause secondary demyelination, some gliosis, and low-grade inflammation, all of which might affect the apparent white matter integrity. It is also unlikely that abnormal oligodendrocytes and myelin constitute the primary cause of these diseases. However, long axons are the bottleneck of neuronal integrity. When axons are stressed, eg, by toxic proteins or other cell-autonomous causes, oligodendrocytes are their closest bystanders. Glia are in a position to influence the susceptibility of diseased axons to undergo degeneration (axonal apoptosis) or to be resistant. Thus, interindividual differences of oligodendrocytes in neuroprotection may be important disease modifiers or contribute to the onset of clinical symptoms. In that sense, oligodendrocytes may be one of several causes of a complex disease. A fresh view on causality came from an unbiased finding5 that oligodendroglial gene transcripts are specifically reduced in schizophrenia brain post mortem. Among several dysregulated myelin genes, CNP1 encodes a remarkable oligodendrocyte-specific protein of themyelin sheath that is not required formyelination per se but formaintainingnormalaxon functionandsurvival.Recently,heterozygousCnp1+/−micethatappearhealthyoverall andare long lived were studiedat thebehavioral level.6 This revealedanunusual phenotype consisting of catatonia and depression-like symptoms, but only at rather old age (>18months). Moreover, white matter tracts showedmany histological signs of normal brain aging, such as axonal swellings,myelindelamination, and low-grade inflammation,but earlier thannormal. Thus,Cnp1heterozygousmiceprovideproof of Clinical Review&Education