The Journal of neuroscience : the official journal of the Society for Neuroscience
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Macrophages have been implicated in peripheral nerve regeneration for some time, supposedly through their involvement in Wallerian degeneration, the process by which the distal nerve degenerates after axotomy and is cleared by phagocytosis. Thus, in several studies in which macrophage accumulation in the distal nerve was reduced and Wallerian degeneration inhibited, regeneration was delayed. However, this interpretation ignores the more recent findings that macrophages also accumulate around axotomized cell bodies. ⋯ In the superior cervical ganglion (SCG), particularly in Wld(s) mice, macrophage accumulation was reduced but not abolished after axotomy. In SCG neurons from Wld(s) mice, the conditioning lesion response was unchanged; however, in CCR2(-/-) mice in which the effect on macrophage accumulation was greater, SCG neurite outgrowth was significantly reduced. These results indicate that macrophages affect neurite outgrowth by acting at the level of peripheral ganglia in addition to any effects they might produce by facilitation of Wallerian degeneration.
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Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. ⋯ Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.
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Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. ⋯ We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.
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Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. ⋯ Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit.
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The ventrolateral periaqueductal gray (vlPAG) is an integral locus for morphine action. Although it is clear that glia contribute to the development of morphine tolerance, to date, the investigation of their role has been limited to spinal and medullary loci. Opioids induce a neuroinflammatory response that opposes acute and long-term analgesia, thereby limiting their efficacy as therapeutic agents. ⋯ Further, antagonizing vlPAG TLR4 dose dependently prevented the development of morphine tolerance, and vlPAG microinjections of TLR4 agonists dose dependently produced a "naive" tolerance to subsequent challenge doses of morphine. Finally, using a model of persistent inflammatory pain and pharmacological manipulation of TLR4 we demonstrate that systemic antagonism of TLR4 potentiated acute morphine antihyperalgesia. These results, together, indicate that vlPAG glia regulate morphine tolerance development via TLR4 signaling, and implicate TLR4 as a potential therapeutic target for the treatment of pain.