Notizen: Several cytokines have short-term effects on synaptic transmission and plasticity that are thought to be mediated by the activation of intracellular protein kinases. We have studied the effects of interleukin-6 (IL-6) on the expression of paired pulse facilitation (PPF), posttetanic potentiation (PTP), and long-term potentiation (LTP) in the CA1 region of the hippocampus as well as on the activation of the signal transducer and activator of transcription-3 (STAT3), the mitogen-activated protein kinase ERK (MAPK/ERK), and the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). IL-6 induced a marked and dose-dependent decrease in the expression of PTP and LTP that could be counteracted by the simultaneous treatment with the tyrosine kinase inhibitor lavendustin A (LavA) but did not significantly affect PPF. The IL-6-induced inhibition of PTP and LTP was accompanied by a simulation of STAT3 tyrosine phosphorylation and an inhibition of MAPK/ERK dual phosphorylation, in the absence of changes in the state of activation of SAPK/JNK. Both effects of IL-6 on STAT3 and MAPK/ERK activation were effectively counteracted by LavA treatment. The results indicate the tyrosine kinases and MAPK/ERK are involved in hippocampal synaptic plasticity and may represent preferential intracellular targets for the actions of IL-6 in the adult nervous system.

Notizen: We used field potential recordings in an in vitro thalamocortical slice preparation to compare the rhythmic oscillations generated by reciprocally connected networks of the thalamus and cerebral cortex obtained from epileptic (〉 160 days old) WAG/Rij and age-matched, nonepileptic control (NEC) rats. To increase neuronal excitability, and thus to elicit spontaneous field potential activity in vitro, we applied medium containing: (i) zero [Mg2+]; (ii) high [K+] (8.25 mm); or (iii) low concentrations of the K+ channel blocker 4-aminopyridine (4AP, 0.5–1 µm). Of these procedures, only the last was effective in triggering oscillatory activity that depended on the type of tissue. Thus, during 4AP application: (i) sequences of fast (intraburst frequency 9.5–16.1 Hz) and slower (5–8.9 Hz) field potential oscillations (FPOs) were recorded in WAG/Rij slices (n = 23), but (ii) only fast FPOs were seen in NEC slices (n = 7). Slower FPOs in WAG/Rij slices reflected a larger degree of thalamocortical synchronization than fast FPOs, and disappeared after surgical separation of cortex and thalamus (n = 5); under these conditions fast FPOs continued to occur in thalamus only. In addition, fast and slower FPOs disappeared in all areas of the WAG/Rij slice during thalamic application of the excitatory amino acid receptor antagonist kynurenic acid (n = 3), while fast FPOs continued to occur in thalamus when kynurenic acid was applied to the cortex (n = 4). Bath application of the N-methyl-d-aspartic acid (NMDA) receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP) abolished slower FPOs in WAG/Rij cortex and thalamus (n = 6) without infuencing fast FPOs recorded in WAG/Rij (n = 6) or NEC slices (n = 4). Moreover, cortical application of CPP (n = 6) abated slower FPOs although they persisted following CPP application to the thalamus (n = 7). Our data demonstrate that highly synchronized, slower FPOs can occur during 4AP application in WAG/Rij but not in NEC slices. This activity, which may represent an in vitro hallmark of thalamocortical epileptogenicity, requires the function of reciprocally connected thalamic and cortical networks and depends on cortical NMDA receptor-mediated mechanisms.

Notizen: Cytokines are extracellular mediators that have been reported to affect neurotransmitter release and synaptic plasticity phenomena when applied in vitro. Most of these effects occur rapidly after the application of the cytokines and are presumably mediated through the activation of protein phosphorylation processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6) has been found to have a neuroprotective effect against ischaemia lesions and glutamate excitotoxicity, and to increase neuronal survival in a variety of experimental conditions. In this paper, the functional effects of IL-6 on the spread of excitation visualized by dark-field/infrared videomicroscopy in rat cortical slices and on glutamate release from cortical synaptosomes were analysed and correlated with the activation of the STAT3, mitogen-activated protein kinase ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase (SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation and evoked glutamate release in the cerebral cortex, and that these effects are accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6 were effectively counteracted by treatment of the cortical slices with the tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on glutamate release and on the spread of excitation in the rat cerebral cortex indicate that the protective effect of IL-6 on neuronal survival could be mediated by a downregulation of neuronal activity, release of excitatory neurotransmitters and MAPK/ERK activity.