Neuroscience
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Although several studies have suggested the neuroprotective effect of thymosin β4 (TB4), a major actin-sequestering protein, on the central nervous system, little is understood regarding the action of N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP), a peptide fragment of TB4 on brain function. Here, we examined neurogenesis-stimulative effect of Ac-SDKP. Intrahippocampal infusion of Ac-SDKP facilitated the generation of new neurons in the hippocampus. ⋯ Moreover, inhibition of vascular endothelial growth factor (VEGF) signaling blocked Ac-SDKP-facilitated neural proliferation. Subchronic intrahippocampal infusion of Ac-SDKP also increased spatial memory. Taken together, these data demonstrate that Ac-SDKP functions as a regulator of neural proliferation and indicate that Ac-SDKP may be a therapeutic candidate for diseases characterized by neuronal loss.
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A total of 211 neurons that discharged at the highest rate during sleep (sleep-active neurons) were recorded in non-anesthetized, head-restrained mice during the complete wake-sleep cycle in, and around, the laterodorsal (LDT) and sublaterodorsal (SubLDT) tegmental nuclei, which contain both cholinergic and non-cholinergic neurons. For the first time in mice, I reveal the presence, mainly in the SubLDT, of sleep-specific neurons displaying sustained tonic discharge either (i) just prior to, and during, paradoxical sleep (PS) (PS-on neurons) or (ii) during both slow-wave sleep (SWS) and PS (SWS/PS-on neurons). Both the PS-on and SWS/PS-on neurons showed either a low (< 10 Hz) or high (⩾ 10 Hz) rate of spontaneous firing and exhibited a biphasic narrow or medium-to-broad action potential, a characteristic of non-cholinergic neurons. ⋯ At the transition from SWS to PS, only the PS-on neurons exhibited a significant increase in discharge rate before PS onset, while, at the transition from PS to W, the SWS/PS-on neurons, then the PS-on neurons, displayed a significant decrease in the discharge rate before the end of PS. The SWS/PS-on neurons were more sensitive to the change in the electroencephalogram (EEG) than the PS-on neurons, as, during a PS episode, the slightest interruption of rhythmic theta activity resulted in cessation of discharge of the SWS/PS-on neurons. These findings support the view that, in the mouse SubLDT, PS-on neurons play an important role in the induction, maintenance, and cessation of PS, while SWS/PS-on neurons play a role in the maintenance of the PS state in particular and the sleep state in general.
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Positive allosteric modulators (PAMs) of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors receive increasing interest as therapeutic drugs and have long served as important experimental tools in the study of the molecular mechanisms underlying glutamate-mediated neurotransmission. The aim of this study was to investigate functional and structural aspects of a novel analog of the AMPA receptor PAM cyclothiazide (CTZ) on recombinant and native glutamate receptors. We expressed rat GluA4flip and flop in Xenopus oocytes and characterized NS1376 and CTZ under two-electrode voltage-clamp. ⋯ Finally, we obtained detailed molecular information through X-ray structures, docking and molecular dynamics, which revealed that NS1376 interacts at the dimer interface of the ligand-binding domain in a manner overall similar to CTZ. NS1376 reveals that minor structural changes in CTZ can result in an altered modulatory profile, both enhancing agonist efficacy while markedly reducing agonist potency. These unique properties add new aspects to the complexity of allosteric modulations in neuronal systems.