Highlights d GABA limits MGE-cIN participation in synchronous network events during development d Synaptic GABA regulates the emergence of interneuronpyramidal cell assemblies d GABAergic restriction of pyramidal cell activity is required for MGE-cIN apoptosis d GABA A g2-containing GABA A receptors are essential for interneuron apoptosis Authors

Intraventricular hemorrhage (IVH) results in neural cell-death and white matter injury in premature infants. No therapeutic strategy is currently available against this disorder. Bone-morphogenetic-protein (BMP) signaling suppresses oligodendrocyte development through basic-helix-loop-helix (bHLH) transcription factors and promotes astrocytosis. Therefore, we hypothesized that IVH in premature newborns initiates degeneration and maturation arrest of oligodendrocyte lineage, and that BMP inhibition alleviates hypomyelination, gliosis, and motor impairment in the survivors of IVH. To test the hypotheses, a rabbit model of IVH was used where premature rabbit pups (E29) are treated with intraperitoneal glycerol at 2 h age to induce IVH; and the pups with IVH exhibit hypomyelination and gliosis at two weeks of postnatal age. Maturation of oligodendrocyte lineage was evaluated by specific markers; and the expression of bHLH transcription factors was assessed. BMP levels were measured in both premature rabbit pups and autopsy materials from premature infants. Recombinant human noggin was used to suppress BMP action; and neurobehavioral performance, myelination and gliosis were assessed in noggin-treated pups compared to untreated controls. We found that IVH resulted in apoptosis and reduced proliferation of oligodendrocyte progenitors, as well as arrested maturation of pre-oligodendrocytes in rabbits. BMP4 levels were significantly elevated in both rabbit pups and human premature infants with IVH compared to controls. Importantly, BMP inhibition by recombinant human noggin restored the levels of phospho-Smad 1/5/8, Olig2 transcription factor, oligodendrocyte maturation, myelination, astrocyte morphology and motor function in premature pups with IVH. Hence, BMP inhibition might enhance neurological recovery in premature infants with IVH.

In rodents, the barrel cortex is a specialized area within the somatosensory cortex that processes signals from the mystacial whiskers. We investigated the normal development of myelination in the barrel cortex of mice, as well as the effects of sensory deprivation on this pattern. Deprivation was achieved by trimming the whiskers on one side of the face every other day from birth. In control mice, myelin was not present until postnatal day 14 and did not show prominence until postnatal day 30; adult levels of myelination were reached by the end of the second postnatal month. Unbiased stereology was used to estimate axon density in the interbarrel septal region and barrel walls as well as the barrel centers. Myelin was significantly more concentrated in the interbarrel septa/barrel walls than in the barrel centers in both control and sensory-deprived conditions. Sensory deprivation did not impact the onset of myelination but resulted in a significant decrease in myelinated axons in the barrel region and decreased the amount of myelin ensheathing each axon. Visualization of the oligodendrocyte nuclear marker Olig2 revealed a similar pattern of myelin as seen using histochemistry, but with no significant changes in Olig2+ nuclei following sensory deprivation. Consistent with the anatomical results showing less myelination, local field potentials revealed slower rise times following trimming. Our results suggest that myelination develops relatively late and can be influenced by sensory experience.