Sonic hedgehog regulates the growth and patterning of the cerebellum.
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The molecular bases of brain development and CNS malignancies remain poorly understood. Here we show that Sonic hedgehog (Shh) signaling controls the development of the cerebellum at multiple levels. SHH is produced by Purkinje neurons, it is required for the proliferation of granule neuron precursors and it induces the differentiation of Bergmann glia. Blocking SHH function in vivo results in deficient granule neuron and Bergmann glia differentiation as well as in abnormal Purkinje neuron development. Thus, our findings provide a molecular model for the growth and patterning of the cerebellum by SHH through the coordination of the development of cortical cerebellar cell types. In addition, they provide a cellular context for medulloblastomas, childhood cancers of the cerebellum. (+info)
N-type calcium channels and their regulation by GABAB receptors in axons of neonatal rat optic nerve.
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Axons of neonatal rat optic nerves exhibit fast calcium transients in response to brief action potential stimulation. In response to one to four closely spaced action potentials, evoked calcium transients showed a fast-rising phase followed by a decay with a time constant of approximately 2-3 sec. By selective staining of axons or glial cells with calcium dyes, it was shown that the evoked calcium transient originated from axons. The calcium transient was caused by influx because it was eliminated when bath calcium was removed. Pharmacological profile studies with calcium channel subtype-specific peptides suggested that 58% of the evoked calcium influx was accounted for by N-type calcium channels, whereas L- and P/Q-type calcium channels had little, if any, contribution. The identity of the residual calcium influx remains unclear. GABA application caused a dramatic reduction of the amplitude of the action potential and the associated calcium influx. When GABAA receptors were blocked by bicuculline, the inhibitory effect of GABA on the action potential was eliminated, whereas that on the calcium influx was not, indicating involvement of GABAB receptors. Indeed, the calcium influx was inhibited by the GABAB receptor agonist baclofen. This baclofen effect was occluded by a previous block of N-type calcium channels and was unaffected by the broad-spectrum K+ channel blocker 4-AP. We conclude that neonatal rat optic nerve axons express N-type calcium channels, which are subjected to regulation by G-protein-coupled GABAB receptors. We suggest that receptor-mediated inhibition of axonal calcium channels plays a protective role in neonatal anoxic and/or ischemic injury. (+info)
The concentration of synaptically released glutamate outside of the climbing fiber-Purkinje cell synaptic cleft.
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AMPA receptors and glutamate transporters expressed by cerebellar Bergmann glial cells are activated by neurotransmitter released from climbing fibers (). Based on anatomical evidence, this is most likely the result of glutamate diffusing out of the climbing fiber-Purkinje cell synaptic clefts (). We used the change in the EC50 of the Bergmann glia AMPA receptors produced by cyclothiazide (CTZ) to estimate the concentration of glutamate reached at the glial membrane. The decrease of the EC50 gives rise to a concentration-dependent potentiation of the AMPA receptor-mediated responses (). By comparing the increase in amplitude of the AMPA receptor response in the Bergmann glia (840 +/- 240%; n = 8) with the shift in the glutamate dose-response curve measured in excised patches (EC50, 1810 microM in control vs 304 microM in CTZ), we estimate that the extrasynaptic transmitter concentration reaches 160-190 microM. This contrasts with the concentration in the synaptic cleft, thought to rapidly rise above 1 mM, but is still high enough to activate glutamate receptors. These results indicate that the sphere of influence of synaptically released glutamate can extend beyond the synaptic cleft. (+info)
Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury.
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We examined the effects of modulating group II metabotropic glutamate receptors (mGluRs) on traumatic neuronal injury using both in vitro and in vivo models. Treatment with various selective group II mGluR agonists significantly decreased lactate dehydrogenase release, a marker of cell death, after traumatic injury to rat neuronal-glial cultures; injury-induced increases in cyclic AMP and glutamate levels were also significantly reduced by a group II agonist. The neuroprotective effects of group II agonists were markedly attenuated by coadministration of a group II antagonist or a membrane-permeable cyclic AMP analog and were additive to those provided by an N-methyl-D-aspartate receptor antagonist or a selective group I mGluR antagonist. Administration of a group II mGluR agonist 30 min after lateral fluid percussion-induced brain injury in rats significantly improved subsequent behavioral recovery as compared with vehicle-treated controls. Together these studies indicate that group II mGluR agonists protect against traumatic neuronal injury by attenuating glutamate release and cAMP levels and suggest a potential role for these agents in the treatment of clinical neurotrauma. (+info)
Regulation of gamma-glutamylcysteine synthetase subunit gene expression in retinal Muller cells by oxidative stress.
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PURPOSE: To study regulation of gamma-glutamylcysteine synthetase (GCS) heavy and light subunit gene expression in Muller cells under conditions of oxidative stress. METHODS: Experiments were carried out with an SV40 transformed cell line (rMC-1) that exhibits the phenotype of rat retinal Muller cells. Endogenous glutathione levels were modified by treating cells with diethyl maleate (DEM), D,L-buthionine sulfoximine (BSO), or tert-butylhydroquinone (TBH). In other experiments, cells were grown in either high (28 mM) or normal (5.5 mM) glucose medium for 1 week to examine the effects of hyperglycemia. Cells were processed for reduced glutathione (GSH) measurement, RNA extraction, cell count, and, in some cases, lactate dehydrogenase activity. The steady state mRNA levels of GCS heavy and light subunits were measured by northern blot analysis using specific cDNA probes. Changes in mRNA levels were normalized to beta-actin or 18S rRNA. RESULTS: Treatment with DEM for 30 minutes depleted cell GSH to 20% to 30% of the normal value. GSH content recovered completely 6 hours after returning to normal medium. BSO treatment for 12 hours followed by a medium change for 6 hours resulted in a cell GSH level that was 26% that of untreated cells. If cells were left in BSO for 18 hours, however, GSH levels were reduced to < 1%. Treatment with TBH for 12 hours led to a 77% increase in cellular GSH level. Treatment with DEM, TBH, or BSO for 18 hours led to a significant induction of the mRNA level of the GCS subunits, regardless of glucose concentration in the medium. Shorter BSO treatment exerted no effect. Prolonged hyperglycemia resulted in 30% lower GSH level, 55% lower GCS heavy subunit, and 30% lower GCS light subunit mRNA levels. CONCLUSIONS: Oxidative stress induced the gene expression of GCS heavy and light subunits in Muller cells. The effect of BSO on mRNA levels correlated with the degree of GSH depletion. Prolonged hyperglycemia lowered GCS subunit mRNA and GSH levels. (+info)
Migration and function of glia in the developing Drosophila eye.
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Although glial cells have been implicated widely in the formation of axon tracts in both insects and vertebrates, their specific function appears to be context-dependent, ranging from providing essential guidance cues to playing a merely facilitory role. Here we examine the role of the retinal basal glia (RBG) in photoreceptor axon guidance in Drosophila. The RBG originate in the optic stalk and have been thought to migrate into the eye disc along photoreceptor axons, thus precluding any role in axon guidance. Here we show the following. (1) The RBG can, in fact, migrate into the eye disc even in the absence of photoreceptor axons in the optic stalk; they also migrate to ectopic patches of differentiating photoreceptors without axons providing a continuous physical substratum. This suggests that glial cells are attracted into the eye disc not through haptotaxis along established axons, but through another mechanism, possibly chemotaxis. (2) If no glial cells are present in the eye disc, photoreceptor axons are able to grow and direct their growth posteriorly as in wild type, but are unable to enter the optic stalk. This indicates that the RBG have a crucial role in axon guidance, but not in axonal outgrowth per se. (3) A few glia close to the entry of the optic stalk suffice to guide the axons into the stalk, suggesting that glia instruct axons by local interaction. (+info)
Central neurocytoma with malignant course. Neuronal and glial differentiation and craniospinal dissemination.
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Central neurocytoma is a benign neuronal tumor of young adults in the lateral cerebral ventricles with characteristic X ray and light microscopic findings. In many respects typical central neurocytoma is reported below, with recurrence in the third month requiring reoperation. Death ensued in the fifth postoperative month. Subsequent histology proved progressive vascular proliferation and increasing, unusual glial differentiation of the neuronal tumor. At autopsy tumorous seeding blocked the liquor circulation. A thin tumorous layer covered the surface of all ventricles, the cerebellum and medulla oblongata. The GFAP positive cells out-numbered the synaptophysin positive ones. Increase of GFAP positivity and vascular proliferation of the central neurocytoma may be alarming signs suggesting a malignant course in addition to the other atypical features. (+info)
Implications of immune-to-brain communication for sickness and pain.
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This review presents a view of hyperalgesia and allodynia not typical of the field as a whole. That is, exaggerated pain is presented as one of many natural consequences of peripheral infection and injury. The constellation of changes that results from such immune challenges is called the sickness response. This sickness response results from immune-to-brain communication initiated by proinflammatory cytokines released by activated immune cells. In response to signals it receives from the immune system, the brain orchestrates the broad array of physiological, behavioral, and hormonal changes that comprise the sickness response. The neurocircuitry and neurochemistry of sickness-induced hyperalgesia are described. One focus of this discussion is on the evidence that spinal cord microglia and astrocytes are key mediators of sickness-induced hyperalgesia. Last, evidence is presented that hyperalgesia and allodynia also result from direct immune activation, rather than neural activation, of these same spinal cord glia. Such glial activation is induced by viruses such as HIV-1 that are known to invade the central nervous system. Implications of exaggerated pain states created by peripheral and central immune activation are discussed. (+info)