Hippocampus
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Pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotrophic and neuromodulatory peptide, was recently shown to enhance NMDA receptor-mediated currents in the hippocampus (Macdonald, et al. 2005. J Neurosci 25:11374-11384). To check if PACAP might also modulate AMPA receptor function, we tested its effects on AMPA receptor-mediated synaptic currents on CA1 pyramidal neurons, using the patch clamp technique on hippocampal slices. ⋯ The inhibitory effect of 10 nM PACAP was mimicked by Bay 55-9837 (a selective agonist of VPAC2 receptors), persisted in the presence of intracellular BAPTA and was abolished by intracellular cAMPS-Rp. Stimulation-evoked EPSCs in CA1 neurons were significantly reduced following application of the PAC1 antagonist PACAP 6-38; this result indicates that PAC1 receptors in the CA1 region are tonically activated by endogenous PACAP and enhance CA3-CA1 synaptic transmission. Our results show that PACAP differentially modulates AMPA receptor-mediated current in CA1 pyramidal neurons by activation of PAC1 and VPAC2 receptors, both involving the cAMP/PKA pathway; the functional significance will be discussed in light of the multiple effects exerted by PACAP on the CA3-CA1 synapse at different levels.
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Our previous study showed that kainate (KA) receptor subunit GluR6 played an important role in ischemia-induced MLK3 and JNK activation and neuronal degeneration through the GluR6-PSD95-MLK3 signaling module. However, whether the KA receptors subunit GluR6 is involved in the activation of p38 MAP kinase during the transient brain ischemia/reperfusion (I/R) in the rat hippocampal CA1 subfield is still unknown. In this present study, we first evaluated the time-course of phospho-p38 MAP kinase at various time-points after 15 min of ischemia and then observed the effects of antagonist of KA receptor subunit GluR6, GluR6 antisence oligodeoxynucleotides on the phosphorylation of p38 MAP kinase induced by I/R. ⋯ These drugs also reduced the phosphorylation of MLK3, MKK3/MKK6, MKK4, and MAPKAPK2. Additionally, our results indicated administration of three drugs, including p38 MAP kinase inhibitor before brain ischemia significantly decreased the number of TUNEL-positive cells detected at 3 days of reperfusion and increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion after 15 min of ischemia. Taken together, we suggest that GluR6-contained KA receptors can mediate p38 MAP kinase activation through a kinase cascade, including MLK3, MKK3/MKK6, and MKK4 and then induce increased phosphorylation of MAPKAPK-2 during ischemia injury and ultimately result in neuronal cell death in the rat hippocampal CA1 region.