Neuroscience
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Our experiments demonstrate a novel role for group I metabotropic glutamate receptor (mGluR) subtypes 1 and 5 in generating a long-lasting synaptic excitation in the substantia gelatinosa (SG) and deep dorsal horn (DH) neurons of the rat spinal cord. In the present study we have investigated a slow excitatory postsynaptic current (EPSC), elicited by a brief high intensity (at Adelta/C fiber strength) and high frequency (20 or 100 Hz) stimulation of primary afferent fibers (PAFs) using whole-cell patch-clamp recordings from neurons located in the DH (laminae II-V) in spinal cord slices of young rats and wild-type and gene-targeted mice lacking mGluR1 subtype. The results shown here suggest that the activation of both mGluR1 and mGluR5 along with NK1 receptors, may be involved in the generation of the slow EPSC in the spinal cord DH. ⋯ Therefore, we conclude, that glutamate transporters strongly influence the group I mGluR activation by PAFs possibly at sensory synapses in the DH. Overall these data indicate that stimulus trains can generate a sustained and widespread glutamate signal that can further elicit prolonged EPSCs predominantly mediated by the group I mGluRs. These slow excitatory synaptic currents may have important functional implications for DH cell firing and synaptic plasticity of sensory transmission, including nociception.
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At the mouse neuromuscular junction, activation of adenosine A(1) and P2Y receptors inhibits acetylcholine release by an effect on voltage dependent calcium channels related to spontaneous and evoked secretion. However, an effect of purines upon the neurotransmitter-releasing machinery downstream of Ca(2+) influx cannot be ruled out. An excellent tool to study neurotransmitter exocytosis in a Ca(2+)-independent step is the hypertonic response. ⋯ On the other hand, the inhibitors of protein kinase A (N-(2[pbromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide, H-89) and phosphoinositide-3 kinase (PI3K) (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride, LY-294002) did not modify the modulatory action in hypertonicity of both purines. Our results provide evidence that activation of A(1) and P2Y(12-13) receptors by CCPA and 2-MeSADP inhibits ACh release from mammalian motor nerve terminals through an effect on a Ca(2+)-independent step in the cascade of the exocytotic process. Since presynaptic calcium channels are intimately associated with components of the synaptic vesicle docking and fusion processes, further experiments could clarify if the actions of purines on calcium channels and on secretory machinery are related.
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We report naturally occurring, systematic variations in synaptic strength at neuromuscular junctions along the dorsal-ventral (D-V) axis of the Drosophila larval body wall. These gradual changes were correlated with differences in presynaptic neurotransmitter release regulated by nerve terminal excitability and in postsynaptic receptor composition influencing miniature excitatory junctional potential (mEJP) amplitude. Surprisingly, synaptic strength and D-V differentials at physiological Ca(2+) levels were not significantly altered in slowpoke (slo) and Shaker (Sh) mutants, despite their defects in two major repolarizing forces, Ca(2+)-activated Slo (BK) and voltage-activated Sh currents, respectively. ⋯ In addition, slo mutants displayed altered immunoreactivity intensity ratio between DGluRIIA and DGluRIIB receptor subunits. This modified receptor composition caused smaller mEJP amplitudes, further preventing excessive transmission in the absence of Slo current. Such compensatory regulations were prevented by rutabaga (rut) adenylyl cyclase mutations in rut slo double mutants, demonstrating a novel role of rut in homeostatic plasticity, in addition to its well-established function in learning behavior.
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Building upon our initial studies in young adult surgically menopausal monkeys, this study examined the effects of a novel schedule of administration of estradiol therapy alone, or in combination with progesterone, on visual and spatial recognition memory in older monkeys. Monkeys were preoperatively trained on a delayed matching-to-sample task and a delayed response task. At the time of ovariectomy, monkeys began their hormonal treatments and were cognitively assessed at 2, 12 and 24 weeks following treatment initiation. ⋯ There was no effect of hormone therapy on accuracy in the delayed response task at any of the postoperative assessments. In both tasks, monkeys treated with estrogen plus progesterone had longer choice response latencies, especially on trials in which they made errors; however these effects did not influence accuracy measures in these animals. Our findings indicate that visual recognition ability may be more sensitive than spatial recognition memory to this novel hormone therapy regimen, that treatment with estradiol plus progesterone was equivalent to that of estradiol alone, and that neither therapy had significant negative impact on memory profiles.
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Neuronal cell death and its regulation have been extensively studied as an essential process of both neurodevelopment and neurodegenerative conditions. However it is not clear how circulating hormones influence such processes. Therefore we aimed to determine whether the anti-obesity hormone leptin could promote the survival of murine central and peripheral neurons in vitro. ⋯ In addition, it promotes the survival of postnatal, but not embryonic, trigeminal sensory neurons following neurotrophin withdrawal. Our data reveal a novel neuroprotective role for leptin in the peripheral nervous system while expanding on the known anti-apoptotic role of leptin in the CNS. These findings have important implications for our understanding of neuronal viability.