Diffuse white matter injury is common in very preterm infants; here, enhanced epidermal growth factor receptor signalling in oligodendrocyte precursor cells in a mouse model of such injury is shown to increase cellular and functional recovery. As the survival rates of premature babies have increased, so too has the incidence of chronic neurodevelopmental disorders in neonates. Diffuse white matter injury is common in preterm infants with neonatal brain injury and is partially the result of a failure in oligodendrocyte precursor cell maturation. Here, Vittorio Gallo and colleagues specifically enhanced epidermal growth factor receptor (EGFR) signalling in oligodendrocyte precursor cells in a model of diffuse white matter injury and found increased cellular and functional recovery post-injury. Oligodendrocyte cell death was decreased and the generation of new oligos was increased by the treatment. This identifies EGFR signalling as a potential therapeutic target in the treatment of premature children after white matter injury. There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks’ gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments1,2. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI3. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development4. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

The authors show that chronic neonatal hypoxia reduces GABAA receptor–mediated signaling to oligodendrocyte precursor cells in the cerebellar white matter and enhances their proliferation, delays oligodendrocyte maturation and disrupts myelination. Following hypoxia, treatment with a GABA uptake blocker restores myelination. Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing oligodendrocyte precursor cells (NG2 cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2 cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor–mediated synaptic input to NG2 cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2 cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2 cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI.

In order to stabilize changes in synaptic strength, neurons activate a program of gene expression that results in alterations of their molecular composition and structure. Here we demonstrate that Fnk and Snk, two members of the polo family of cell cycle associated kinases, are co‐opted by the brain to serve in this program. Stimuli that produce synaptic plasticity, including those that evoke long‐term potentiation (LTP), dramatically increase levels of both kinase mRNAs. Induced Fnk and Snk proteins are targeted to the dendrites of activated neurons, suggesting that they mediate phosphorylation of proteins in this compartment. Moreover, a conserved C‐terminal domain in these kinases is shown to interact specifically with Cib, a Ca²⁺‐ and integrin‐binding protein. Together, these studies suggest a novel signal transduction mechanism in the stabilization of long‐term synaptic plasticity.

NG2 proteoglycan+ cells are neural and oligodendrocyte progenitors, and NG2+ cells in the developing barrel cortex receive glutamatergic thalamocortical inputs. Here, the authors show that NG2+ cells are primarily localized in barrel septa and that sensory deprivation induces NG2+ cell proliferation and differential localization in and around the barrels. We found that, during the formation of the mouse barrel cortex, NG2 cells received glutamatergic synapses from thalamocortical fibers and preferentially accumulated along septa separating the barrels. Sensory deprivation reduced thalamocortical inputs on NG2 cells and increased their proliferation, leading to a more uniform distribution in the deprived barrels. Thus, early sensory experience regulates thalamocortical innervation on NG2 cells, as well as their proliferation and distribution during development.