Leukemia inhibitory factor (LIF) promotes the survival of oligodendrocytes both in vitro and in an animal model of multiple sclerosis, but the possible role of LIF signaling in myelination during normal development has not been investigated. We find that LIF(-/-) mice have a pronounced myelination defect in optic nerve at postnatal day 10. Myelin basic protein (MBP)- and proteolipid protein (PLP)-positive myelin was evident throughout the optic nerve in the wild-type mice, but staining was present only at the chiasmal region in LIF(-/-) mice of the same age. Further experiments suggest that the myelination defect was a consequence of a delay in maturation of oligodendrocyte precursor cell (OPC) population. The number of Olig2-positive cells was dramatically decreased in optic nerve of LIF(-/-) mice, and the distribution of Olig2-positive cells was restricted to the chiasmal region of the nerve in a steep gradient toward the retina. Gene expression profiling and cell culture experiments revealed that OPCs from P10 optic nerve of LIF(-/-) mice remained in a highly proliferative immature stage compared with littermate controls. Interestingly, by postnatal day 14, MBP immunostaining in the LIF(-/-) optic nerve was comparable to that of LIF(+/+) mice. These results suggest that, during normal development of mouse optic nerve, there is a defined developmental time window when LIF is required for correct myelination. Myelination seems to recover by postnatal day 14, so LIF is not necessary for the completion of myelination during postnatal development.(c) 2009 Wiley-Liss, Inc.

Myelination is a highly dynamic process that continues well into adulthood in humans. Several recent gene expression studies have found abnormal expression of genes involved in myelination in the prefrontal cortex of brains from patients with schizophrenia and other psychiatric illnesses. Defects in myelination could contribute to the pathophysiology of psychiatric illness by impairing information processing as a consequence of altered impulse conduction velocity and synchrony between cortical regions carrying out higher level cognitive functions. Myelination can be altered by impulse activity in axons and by environmental experience. Psychiatric illness is treated by psychotherapy, behavioral modification, and drugs affecting neurotransmission, raising the possibility that myelinating glia may not only contribute to such disorders, but that activity-dependent effects on myelinating glia could provide one of the cellular mechanisms contributing to the therapeutic effects of these treatments. This review examines evidence showing that genes and gene networks important for myelination can be regulated by functional activity in axons.

Activity-dependent signaling between neurons and astrocytes contributes to experience-dependent plasticity and development of the nervous system. However, mechanisms responsible for neuron-glial interactions and the releasable factors that underlie these processes are not well understood. The pro-inflammatory cytokine, leukemia-inhibitory factor (LIF), is transiently expressed postnatally by glial cells in the hippocampus and rapidly up-regulated by enhanced neural activity following seizures. To test the hypothesis that spontaneous neural activity regulates glial development in hippocampus via LIF signaling, we blocked spontaneous activity with the sodium channel blocker tetrodotoxin (TTX) in mixed hippocampal cell cultures in combination with blockers of LIF and purinergic signaling. TTX decreased the number of GFAP-expressing astrocytes in hippocampal cell culture. Furthermore, blocking purinergic signaling by P2Y receptors contributed to reduced numbers of astrocytes. Blocking activity or purinergic signaling in the presence of function-blocking antibodies to LIF did not further decrease the number of astrocytes. Moreover, hippocampal cell cultures prepared from LIF -/- mice had reduced numbers of astrocytes and activity-dependent neuron-glial signaling promoting differentiation of astrocytes was absent. The results show that endogenous LIF is required for normal development of hippocampal astrocytes, and this process is regulated by spontaneous neural impulse activity through the release of ATP.

Two long-standing rules in cellular neuroscience must now be amended with the publication of two studies on myelin-forming glia in the CNS: 1) Neurons can no longer be considered the only cells that fire electric impulses in the brain. 2) Synapses between neurons are not the only way electrical information is regulated as it propagates through neural circuits: oligodendrocytes can cause rapid activity-dependent changes in spike latency. A category of oligodendrocyte precursor cells (OPCs) has been identified that can fire action potentials, and their excitation is driven by synapses from axons. This finding has relevance to excitotoxicity in ischemia, but the normal function may be to regulate myelination according to functional activity in axons. A second study reveals that action potential propagation through CNS axons can be rapidly regulated by oligodendrocytes. Mature oligodendrocytes in the rat hippocampus are depolarized by theta burst stimulation of axons, and when the oligodendrocytes are depolarized by current injection in paired whole-cell recordings with CA1 pyramidal neurons, the latency of impulse conduction through the axons it ensheathes rapidly decreases. This unprecedented finding suggests a dynamic role for myelin in regulating impulse transmission through axons, promoting neural synchrony among the multiple axons under the domain of an individual oligodendrocyte.

"Of what use a newborn babe?" was Oersted's response to a question from the audience as to the value of electromagnetism following his demonstration that a compass needle could be deflected by passing current through a nearby wire. Such is the immediate reaction anytime something new is encountered: What is it, and why do we need it? This perplexity arises from the certain conclusion of a proof derived from the objective facts: we seem to have managed quite well up to now without it. But as functional as a world before cell phones and email seemed, how dysfunctional would the world now appear without them? Time changes, and Science is change. Scientific journals track and pioneer those changes.</g.

White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.

A variety of anatomical features suggest that functional activity in the nervous system can influence the process of myelination, yet direct evidence of this is lacking. Research by Zalc and colleagues shows that myelination of optic nerve is inhibited by a neurotoxin that blocks action potential activity and is stimulated by a toxin that increases impulse activity, suggesting that impulse activity is necessary for initiating myelination during development of the optic nerve. Research by Fields and colleagues, using electrical stimulation of axons, shows that low frequency impulse activity inhibits myelination of dorsal root ganglion neurons, but high frequency impulse activity has no effect. This results from reduced expression of a cell adhesion molecule on the stimulated axons that is critical for inducing myelination. Together these studies support the conclusion that impulse activity can influence the process of myelination, probably through more than one molecular mechanism operating during discrete steps in the myelination process.