Neuroscience
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Gap junctions between glial cells in mammalian CNS are known to contain several connexins (Cx), including Cx26, Cx30 and Cx43 at astrocyte-to-astrocyte junctions, and Cx29 and Cx32 on the oligodendrocyte side of astrocyte-to-oligodendrocyte junctions. Recent reports indicating that oligodendrocytes also express Cx47 prompted the present studies of Cx47 localization and relationships to other glial connexins in mouse CNS. In view of the increasing number of connexins reported to interact directly with the scaffolding protein zonula occludens-1 (ZO-1), we investigated ZO-1 expression and Cx47/ZO-1 interaction capabilities in brain, spinal cord and Cx47-transfected HeLa cells. ⋯ ZO-1 was found to co-immunoprecipitate with Cx47, and pull-down assays indicated binding of Cx47 to the second PDZ domain of ZO-1. Our results indicate widespread expression of Cx47 by oligodendrocytes, but with a distribution pattern in relative levels inverse to the abundance of Cx29 in myelin and paucity of Cx29 in oligodendrocyte somata. Further, our findings suggest a scaffolding and/or regulatory role of ZO-1 at the oligodendrocyte side of astrocyte-to-oligodendrocyte gap junctions.
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Small-diameter sensory neurons are key contributors in joint pain and have been implicated in the pathogenesis of rheumatoid arthritis (RA). Small-diameter sensory neurons can be separated into at least two distinct populations, which include isolectin B4 (IB4)-binding and tyrosine receptor kinase (trk) A-expressing. While trkA-expressing neurons have been identified in the rat knee joint there are no data, we are aware of, to suggest that IB4-binding neurons are also present. ⋯ Injection of FG into skin over the medial aspect of the rat knee (n=3) showed 48% of these cutaneous afferents in L3 and L4 DRG were double-labeled with FG and FITC. A complete absence of IB4-binding neurons in the rat knee joint makes it unlikely that this predominantly cutaneous, IB4-binding population of afferent neurons could have any significant influence in chronic inflammatory joint disease. This suggests that trkA-expressing neurons are the sole population of small-diameter sensory neurons in the knee joint and implies a significant role for these afferents in the progression of RA.
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We have examined the effect of riluzole, a neuroprotective agent with anticonvulsant properties, on the release of endogenous glutamate from rat cerebrocortical synaptosomes using an on-line enzyme-coupled fluorometric assay. Riluzole inhibited the calcium-dependent release of glutamate that was evoked by exposing cerebrocortical synaptosomes to the potassium channel blocker 4-aminopyridine, and this presynaptic inhibition was concentration-dependent. Riluzole did not alter either 4-aminopyridine-evoked depolarization of the synaptosomal membrane potential or ionomycin-mediated glutamate release, indicating that riluzole-mediated inhibition of glutamate release is not due to a decrease in synaptosomal excitability or a direct effect on the exocytotic machinery. ⋯ It is concluded that riluzole exerts their presynaptic inhibition, likely through a reduction in the calcium influx mediated by P/Q-type calcium channels, and thereby inhibits the release of glutamate from rat cerebrocortical nerve terminals. This release inhibition may involve a pertussis toxin-sensitive G protein signalling pathway. This finding provides further support that presynaptic calcium channel blockade concomitant with inhibition of glutamate release could be an important mechanism underlying the therapeutic actions of this drug.
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5-Hydroxytryptamine(1A) (5-HT1A) receptor activation reduces body temperature partially by dilating the thermoregulatory cutaneous vascular bed, thereby increasing heat transfer to the environment. Constriction of this vascular bed, with consequent reduction of heat transfer to the environment, contributes to fever associated with the acute inflammatory response. Thus activation of 5-HT1A receptors might inhibit thermoregulatory cutaneous vasoconstriction and reduce the fever associated with the acute inflammatory response. ⋯ Treatment with WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) (0.1 mg/kg i.v.) prevented and reversed the effects of 8-OH-DPAT. Thus activation of 5-HT1A receptors reduces thermoregulatory cutaneous vasoconstriction and fever occurring as part of the acute inflammatory response. Our findings elucidate the neurotransmitter mechanisms underlying expression of an important component of the febrile response, and suggest that drugs with 5-HT1A agonist properties might be therapeutically useful when it is clinically important to reduce this response.
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Comparative Study
Urocortin expression in the Edinger-Westphal nucleus is down-regulated in transgenic mice over-expressing neuronal corticotropin-releasing factor.
In recent years a large body of evidence has emerged linking chronic stress with increased vulnerability for depression and anxiety disorders. As corticotropin-releasing factor (CRF) is hypersecreted under these psychological conditions, we used our CRF-overexpressing (CRF-OE) mouse line to study underlying brain mechanisms possibly causing these disorders. Urocortin (Ucn), a recently discovered member of the CRF peptide family may play a role in the pathophysiology of stress-induced disorders. ⋯ Our results support this hypothesis as we found weaker immunohistochemical labeling with anti-Ucn and a six times weaker Ucn mRNA signal in E-WN in CRF-OE mice. Moreover, E-WN Ucn-expressing neurons mounted a response to acute challenge in CRF-OE mice too. From these results it is concluded that the CRF and E-WN Ucn neuronal systems work in concert in response to acute challenges, but are inversely regulated in their activities during chronic hyperactivity of the hypothalamo-pituitary-adrenal axis.