A Critical Period for Glia The brain develops in fits and starts—while one system is completed, another system may still be under construction. Such transient states are known as critical periods, and during these specific aspects of brain development may become more sensitive to outside agents than they would be later. Makinodan et al. (p. 1357 ) observed the effect of environmental conditions on the brains of mice bioengineered to develop fluorescent oligodendrocytes. The mice were exposed to a variety of social conditions during rearing, ranging from isolation to a normal laboratory cage setting, or to settings enriched with extra buddies and a steady rotation of new play toys. The results show that social isolation leaves a developmental trace that persists into adulthood. Specifically, they found that oligodendrocytes, which produce the myelin that insulates neurons, were underdeveloped, suggesting that there may be a critical period that governs development of these glial oligodendrocyte cells.

Treatment of neuropathic pain, triggered by multiple insults to the nervous system, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood 1-4 . Most treatments do not differentiate between different phases of neuropathic pain pathophysiology and simply focus on blocking neurotransmission, producing transient pain relief. Here, we report that early and late phase neuropathic pain development after nerve injury require different matrix metalloproteinases (MMPs). After spinal nerve ligation, MMP-9 shows a rapid and transient upregulation in injured DRG primary sensory neurons consistent with an early phase of neuropathic pain, whereas MMP-2 shows a delayed response in DRG satellite cells and spinal astrocytes consistent with a late phase of neuropathic pain. Local inhibition of MMP-9 via an intrathecal route inhibits the early phase of neuropathic pain, whereas inhibition of MMP-2 suppresses late phase of neuropathic pain. Further, intrathecal administration of MMP-9 or MMP-2 is sufficient to produce neuropathic pain symptoms. Following nerve injury, MMP-9 induces neuropathic pain through interleukin-1β cleavage and microglia activation at early times, whereas MMP-2 maintains neuropathic pain through interleukin-1β cleavage and astrocyte activation at later times. Inhibition of MMP may provide a novel therapeutic approach for the treatment of neuropathic pain at different phases.Matrix metalloproteinases (MMPs) are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases through the cleavage of the extracellular matrix proteins, cytokines, and chemokines 5-10 . We hypothesized that neuropathic pain and neuroinflammation may share similar mechanisms. Therefore, we set out to study the roles of the two major gelatinases MMP-2 and MMP-9, in the pathophysiology of neuropathic pain using a well-characterized animal model of L5 spinal nerve ligation (SNL) 11 .Since nerve injury-induced changes in the dorsal root ganglion (DRG) are essential for the generation of neuropathic pain 1 , we examined gelatinase activity in injured (L5) DRGs.

Eph receptors transduce short-range repulsive signals for axon guidance by modulating actin dynamics within growth cones. We report the cloning and characterization of ephexin, a novel Eph receptor-interacting protein that is a member of the Dbl family of guanine nucleotide exchange factors (GEFs) for Rho GTPases. Ephrin-A stimulation of EphA receptors modulates the activity of ephexin leading to RhoA activation, Cdc42 and Rac1 inhibition, and cell morphology changes. In addition, expression of a mutant form of ephexin in primary neurons interferes with ephrin-A-induced growth cone collapse. The association of ephexin with Eph receptors constitutes a molecular link between Eph receptors and the actin cytoskeleton and provides a novel mechanism for achieving highly localized regulation of growth cone motility.