Neuroscience
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Receptor interacting protein (RIP)-1 kinase activity mediates a novel pathway that signals for regulated necrosis, a form of cell death prominent in traumatic and ischemic brain injury. Recently, we showed that an allosteric inhibitor of RIP-1 kinase activity, necrostatin-1 (Nec-1), provides neuroprotection in the forebrain following neonatal hypoxia-ischemia (HI). Because Nec-1 also prevents early oxidative injury, we hypothesized that mechanisms involved in this neuroprotection may involve preservation of mitochondrial function and prevention of secondary energy failure. ⋯ Up-regulation of glial fibrillary acidic protein (GFAP) following HI was also prevented by Nec-1 treatment. No differences by gender were observed. We conclude that Nec-1 immediately after HI, is strongly mitoprotective and prevents secondary energy failure by blocking early NO• accumulation, glutathione oxidation and attenuating mitochondrial dysfunction.
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The clustered protocadherin genes encode a diverse collection of neuronal cell surface receptors. These genes have been proposed to play roles in axon targeting, synaptic development and neuronal survival, although their specific cellular roles remain poorly defined. In zebrafish there are four clustered protocadherin genes, two pcdhα clusters and two pcdhγ clusters, that give rise to over 100 distinct proteins, each with a distinct ectodomain (EC). ⋯ Consistent with studies in mouse, we find that Pcdhα and Pcdhγ are present in a complex, as they can be co-immunoprecipitated from zebrafish larval extracts. This interaction is direct and occurs through the ECs of these proteins. Using standard bead aggregation assays, we find no evidence for intrinsic adhesive ability by either Pcdhγ or Pcdhα, suggesting that they do not function as cell adhesion molecules.
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Biochemical investigations have demonstrated that nitric oxide synthase (NOS) is distributed widely in the olfactory system. However, little is known about the action of NO at the synaptic level on identified neurons in local circuits that process chemosensory signals. Here, using whole-cell recordings, the effect of NO on cholinergic synaptic input to olfactory projection neurons (PNs) is determined in the Drosophila antennal lobes (ALs), which has become an excellent model for studying early olfactory-processing mechanisms. ⋯ The effect of SNP on the frequency of mEPSCs could be eliminated by ODQ as well. Thus, these results suggest that elevated NO concentration decreased cholinergic synaptic input to PNs in a sGC-dependent manner. In this way, NO signaling is suited to fulfill a regulatory role to effectively fine-tune network activity in Drosophila ALs.
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A neuron's phase response curve (PRC) shows how inputs arriving at different times during the spike cycle differentially affect the timing of subsequent spikes. Using a full morphological model of a globus pallidus (GP) neuron, we previously demonstrated that dendritic conductances shape the PRC in a spike frequency-dependent manner, suggesting different functional roles of perisomatic and distal dendritic synapses in the control of patterned network activity. In the present study we extend this analysis to examine the impact of physiologically realistic high conductance states on somatic and dendritic PRCs and the time course of spike train perturbations. ⋯ Therefore, we analyzed the interactions of PRC stimuli with transient fluctuations in the synaptic background on a trial-by-trial basis. We found that the variability in responses to PRC stimuli and the incidence of stimulus-evoked added or skipped spikes were stimulus-phase-dependent and reflected the profile of the average PRC, suggesting commonality in the underlying mechanisms. Clear differences in the relation between the phase of input and variability of spike response between dendritic and somatic inputs indicate that these regions generally represent distinct dynamical subsystems of synaptic integration with respect to influencing the stability of spike time attractors generated by the overall synaptic conductance.
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The functional role of serotonergic 5-HT(1A) receptors in the modulation of visceral pain is controversial. The objective of this study was to systematically examine the mechanism and site of action of a selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (DPAT) on visceral pain. In the behavioral model of visceral pain, systemic injection (5-250 μg/kg) of DPAT produced a significant increase in the viscero-motor response (VMR) to colorectal distension (CRD) and this effect was blocked by the selective 5-HT(1A) receptor antagonist WAY-100135 (5 mg/kg, s.c.). ⋯ In electrophysiology experiments, DPAT (50 μg/kg) significantly increased the responses of spinal neurons to CRD, but did not influence the mechanotransduction property of CRD-sensitive pelvic nerve afferent fibers. The effect of DPAT on spinal neurons remained unaffected when tested in spinal-transected (C1-C2) rats. These results indicate that the 5-HT(1A) receptor agonist DPAT produces pronociceptive effects, primarily via the activation of presynaptic 5-HT(1A) receptors in GABAergic neuron to restrict GABA release and thereby disinhibits the excitatory glutamatergic neurons in the spinal cord.