Synaptic Adhesion Molecules Regulate the Integration of New Granule Neurons in the Postnatal Mouse Hippocampus and their Impact on Spatial Memory.

Postnatal hippocampal neurogenesis induces network remodeling and may participate to mechanisms of learning. In turn, the maturation and survival of newborn neurons is regulated by their activity. Here, we tested the effect of a cell-autonomous overexpression of synaptic adhesion molecules on the maturation and survival of neurons born postnatally and on hippocampal-dependent memory performances. Families of adhesion molecules are known to induce pre- and post-synaptic assembly. Using viral targeting, we overexpressed three different synaptic adhesion molecules, SynCAM1, Neuroligin-1B and Neuroligin-2A in newborn neurons in the dentate gyrus of 7- to 9-week-old mice. We found that SynCAM1 increased the morphological maturation of dendritic spines and mossy fiber terminals while Neuroligin-1B increased spine density. In contrast, Neuroligin-2A increased both spine density and size as well as GABAergic innervation and resulted in a drastic increase of neuronal survival. Surprisingly, despite increased neurogenesis, mice overexpressing Neuroligin-2A in new neurons showed decreased memory performances in a Morris water maze task. These results indicate that the cell-autonomous overexpression of synaptic adhesion molecules can enhance different aspects of synapse formation on new neurons and increase their survival. Furthermore, they suggest that the mechanisms by which new neurons integrate in the postnatal hippocampus conditions their functional implication in learning and memory

Shedding of neurexin 3 beta ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3 beta is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease.-secretase, producing secreted neurexin3 beta (sNrxn3 beta) and a single intracellular domain (Nrxn3 beta-ICD). We further completed the full characterization of the sites at which Nrxn3 beta is processed by these proteases. Supporting the physiological relevance of the Nrxn3 beta processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3 beta on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3 beta produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3 beta produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3 beta in plasticity and network remodeling during neuronal development

Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene

Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5' UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs. Neurons derived from methylation-edited FXS iPSCs rescued the electrophysiological abnormalities and restored a wild-type phenotype upon the mutant neurons. FMR1 expression in edited neurons was maintained in vivo after engrafting into the mouse brain. Finally, demethylation of the CGG repeats in post-mitotic FXS neurons also reactivated FMR1. Our data establish that demethylation of the CGG expansion is sufficient for FMR1 reactivation, suggesting potential therapeutic strategies for FXS

Total-body irradiation before bone marrow transplantation. Results of two randomized instantaneous dose rates in 157 patients

One hundred fifty-seven patients referred to the Department of Radiation Oncology of the Hopital Tenon, Paris, France, between December 10, 1986 and December 31, 1989 for total-body irradiation (TBI) were treated according to the following two techniques: (1) either in one fraction (1000 cGy administered to the midplane at L4 and 800 cGy to the lungs) or (2) in six fractions (1200 cGy on 3 consecutive days to the midplane at L4 and 900 cGy to the lungs). The patients were randomized according to two instantaneous dose rates, called LOW and HIGH, in single-dose (6 versus 15 cGy/min) and hexafractionated (3 versus 6 cGy/min) TBI groups. There were 77 patients in the LOW group and 80 in the HIGH group, with 57 patients receiving single-dose TBI (28 LOW and 29 HIGH) and 100 patients receiving fractionated-dose TBI (49 LOW and 51 HIGH). In March 1991, the 4-year relapse-free and overall survival rates were 58.4% and 52.1%, respectively. The 4-year relapse-free survival and survival rates were 54.9% and 50.7% in the LOW group; 61.9% and 53.5% in the HIGH group (P = 0.69 and 0.82, respectively); 60.3% and 50.4% in the single-dose group; and 57.9% and 53.3% in the fractionated group (P = 0.65 and 0.78, respectively). There was no difference in the incidence of graft versus host disease, interstitial pneumonitis, or venoocclusive disease either between the LOW and the HIGH groups or between the single-dose and fractionated-dose TBI groups. The 4-year estimated cataract incidence was significantly higher in the single-dose HIGH instantaneous dose rate group than in the LOW instantaneous dose rate TBI group (P = 0.049). Multivariate analyses showed that instantaneous dose rate and fractionation do not influence the relapse-free and overall survival rates or the incidence of interstitial pneumonitis