Loss of Tiparp results in aberrant layering of the cerebral cortex

Yes2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase (TIPARP) is an enzyme that adds a single ADP-ribose moiety to itself or other proteins. Tiparp is highly expressed in the brain; however, its function in this organ is unknown. Here, we used Tiparp–/– mice to determine Tiparp’s role in the development of the prefrontal cortex. Loss of Tiparp resulted in an aberrant organization of the mouse cortex, where the upper layers presented increased cell density in the knock-out mice compared with wild type. Tiparp loss predominantly affected the correct distribution and number of GABAergic neurons. Furthermore, neural progenitor cell proliferation was significantly reduced. Neural stem cells (NSCs) derived from Tiparp–/– mice showed a slower rate of migration. Cytoskeletal components, such as α-tubulin are key regulators of neuronal differentiation and cortical development. α-tubulin mono-ADP ribosylation (MAR) levels were reduced in Tiparp–/– cells, suggesting that Tiparp plays a role in the MAR of α-tubulin. Despite the mild phenotype presented by Tiparp–/– mice, our findings reveal an important function for Tiparp and MAR in the correct development of the cortex. Unravelling Tiparp’s role in the cortex, could pave the way to a better understanding of a wide spectrum of neurological diseases which are known to have increased expression of TIPARP.European Union Seventh Framework Program (FP7-PEOPLE-2013-COFUND) Grant n609020-Scientia Fellows (to G.G.) and by the Johan Throne Holst Foundation and the University of Oslo (J.M.)

Modulation of glycinergic transmission in the rat spinal dorsal commissural nucleus by ginkgolide B

The action of ginkgolide B (GB), the powerful compound of Ginkgo biloba extract, on glycinemediated spontaneous currents in rat spinal sacral dorsal commissural nucleus (SDCN) neurons was examined. IPSCs evoked in spinal cord slices were inhibited in a dose-dependent manner by the addition of GB to the superfusion solution. The amplitude of eIPSCs was reduced to 61 ± 6.4% by 10 μM GB, with acceleration of the kinetics of the currents indicating the effect of GB on channel pores. Both the amplitude and success ratio (Rsuc) of eIPSC induced by electrical focal stimulation of single glycinergic nerve endings (boutons) also decreased in the presence of 1 μM GB. These data suggest that GB modulates not only post-synaptic glycine receptors but also the pre-synaptic glycine release mac hinery.Вплив гінкголіду В (GB) – діючої сполуки екстракту з гінкго дволопатевого (Ginkgo biloba) на гліцинопосередковані синаптичні струми вивчався на нейронах спінального сакрального дорсального комісурального ядра (SDCN) щурів. Гальмівні постсинаптичні струми (ГПСС), викликані в препаратах зрізів спинного мозку, дозозалежно зменшувалися при аплікації GB. Амплітуда викликаних ГПСС під дією 10 мкМ GB падала до 61 ± 6.4 % з одночасним прискоренням кінетики струмів, що свідчило про наявність впливу на канальні пори. Як амплітуда, так і відносна кількість синаптичних подій (викликаних ГПСС), індукованих електричною фокальною стимуляцією поодиноких гліцинергічних нервових закінчень (бутонів), також зменшувались у присутності 1 мкМ GB. Ці результати свідчать, що GB не тільки модулює постсинаптичні гліцинові рецептори, але й впливає на пре синаптичні механізми вивільнення гліцину

Ginkgolide B and bilobalide block the pore of the 5-HT3 receptor at a location that overlaps the picrotoxin binding site

Extracts from the Ginkgo biloba tree are widely used as herbal medicines, and include bilobalide (BB) and ginkgolides A and B (GA and GB). Here we examine their effects on human 5-HT3A and 5-HT3AB receptors, and compare these to the effects of the structurally related compounds picrotin (PTN) and picrotoxinin (PXN), the two components of picrotoxin (PTX), a known channel blocker of 5-HT3, nACh and GABAA receptors. The compounds inhibited 5-HT-induced responses of 5-HT3 receptors expressed in Xenopus oocytes, with IC50 values of 470 μM (BB), 730 μM (GB), 470 μM (PTN), 11 μM (PXN) and >1 mM (GA) in 5-HT3A receptors, and 3.1 mM (BB), 3.9 mM (GB), 2.7 mM (PTN), 62 μM (PXN) and >1 mM (GA) in 5-HT3AB receptors. Radioligand binding on receptors expressed in HEK 293 cells showed none of the compounds displaced the specific 5-HT3 receptor antagonist [3H]granisetron, confirming that they do not act at the agonist binding site. Inhibition by GB at 5-HT3A receptors is weakly use-dependent, and recovery is activity dependent, indicating channel block. To further probe their site of action at 5-HT3A receptors, BB and GB were applied alone or in combination with PXN, and the results fitted to a mathematical model; the data revealed partially overlapping sites of action. We conclude that BB and GB block the channel of the 5-HT3A receptor. Thus these compounds have comparable, although less potent, behaviour than at some other Cys-loop receptors, demonstrating their actions are conserved across the family