Differential expression of phospholipase D isozymes in the hippocampus following kainic acid-induced seizures.
ABSTRACT To investigate the pathophysiological role of phospholipase D (PLD)-mediated signaling, changes in the expression of the PLD isozymes PLD1 and PLD2 were investigated in the rat kainic acid (KA) model of human temporal lobe epilepsy. Western blot analysis showed a significant increase in the expression of PLD1 and PLD2 in the postictal hippocampus. PLD1 immunoreactivity increased preferentially in the CA3 and CA1 regions, where pyramidal neurons are susceptible to temporal lobe epilepsy. Experiments employing double immunofluorescence revealed that the cells expressing PLD1 were GFAP-expressing reactive astrocytes. By contrast, PLD2 immunoreactivity increased strikingly in infrapyramidal, but not in suprapyramidal granule cells of the postictal dentate gyrus, fitting well with results of the PLD activity assay. Considering that PLD belongs to a key signaling pathway, this result suggests that changes in granule cell activity in the dentate gyrus after seizures occurs specifically between the supra- and infrapyramidal blades. In addition, enhanced immunoreactivity of PLD2 was observed in the reactive astrocytes of the CA1, CA3, and hilar subregions, but its temporal pattern is different from that of PLD1. Taken together, our results suggest that PLD1 and PLD2 exercise their unique pathophysiological functions in the rat hippocampus after KA-induced seizures.
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ABSTRACT: IL-1β is a potent proinflammatory and immune-regulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1β in synoviocytes from RA is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1) but not PLD2, is selectively upregulated in the IL-1β-stimulated synoviocytes as well as synovium from RA patients. IL-1β enhanced the binding of NFκB and ATF-2 to PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished IL-1β-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NFκB or HIF-1α to the promoter of its target genes as well as IL-1β-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL-1 receptor antagonist deficient mice (IL-1Ra-/-), a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1β-induced chronic arthritis, and a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders.Molecular and cellular biology 05/2013; · 6.06 Impact Factor
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ABSTRACT: If the hippocampus plays a role in the detection of novel environmental features, then novelty should be associated with altered hippocampal neural activity and perhaps also measures of neuroplasticity. We examined Fos protein expression within subregions of rat hippocampal formation as an indicator of recent increases in neuronal excitation and cellular processes that support neuroplasticity. Environmental novelty, but not environmental complexity, led to a selective increase of Fos induction in the final "output" subregion of the dorsal hippocampal trisynaptic circuit (CA1) and a primary projection site (layer five of the lateral entorhinal cortex, ERC), as well as in the perirhinal cortex. There was no selective effect of novelty on Fos expression within "input" elements of the trisynaptic circuit (ERC layer two, the dentate gyrus or CA3) or other comparison brain regions that may be responsive to overall motor-sensory activity or anxiety levels (primary somatosensory and motor cortex or hypothalamic paraventricular nucleus). Test session ambulatory behavior increased with both novelty and environmental complexity and was not significantly correlated with Fos expression patterns in any of the brain regions examined. In contrast, the extent of manipulated environmental novelty was strongly correlated with Fos expression in CA1. These results support the prospect that a novelty-associated signal is generated within hippocampal neurocircuitry, is relayed to cortical projection sites, and specifically up-regulates neuroplasticity-supporting processes with dorsal hippocampal CA1 and ERC layer five. Whether novelty-dependent Fos induction in perirhinal cortex depends on this hippocampal output or reflects an independent process remains to be determined.Learning & memory (Cold Spring Harbor, N.Y.) 02/2008; 15(12):899-908. · 4.08 Impact Factor
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ABSTRACT: Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism.Experimental and Molecular Medicine 04/2011; 43(5):231-74. · 2.57 Impact Factor