Abstracts

Rationale: Clinical observations and experimental studies suggest that central nervous system (CNS) inflammation plays a role in the pathogenesis of epileptic seizures and status epilepticus. For the majority of inflammatory mediators, there is insufficient data so far regarding their effect on epileptogenesis. The chemokine CXCL10, acting via its receptor CXCR3, is involved in the pathophysiological course of several neuroinflammatory conditions (such as viral encephalitis), as well as in neurodegenerative disease associated with an inflammatory component. Most of these conditions are also associated with an increased incidence of seizures or epilepsy. CXCR3 is expressed by resident CNS cells such as microglia and astrocytes, as well as hippocampal and neocortical pyramidal cell. Neuronal CXCR3 receptor activation induces increase of intracellular calcium concentration and depolarization, suggesting that it may contribute to hyperexcitability in inflammatory conditions. The aim of this study was to test the hypothesis that CXCL10, via its receptor CXCR3, increases excitability of a synaptic connection which is part of the mesial temporal network. Methods: Hippocampal slices were prepared from wild type (WT) mice, and transgenic CXCR3 knock-out (KO) mice, respectively. Field excitatory postsynaptic potentials (fEPSP) were elicited by Schaffer collateral stimulation and recorded in the CA1 region. Long-term potentiation (LTP) was induced by tetanic stimulation (10 trains of 4 pulses at 100 Hz, 200 ms apart). LTP was operationally defined as the mean change in fEPSP amplitude for five intensity stimuli applied beginning 30 min after tetanic stimulation, compared with the mean response to five test pulses given immediately before the stimulation. CXCL10 (100 nmol) was applied to the bath solution 8-12 minutes before tetanic stimulation in a subset of experiments. LTP with and without CXCL10 was compared in pairs of slices taken from the same animal. Data was tested for statistical significance using t-test for paired samples. The significance level was set at p<0.05. Results: In slices prepared from WT mice (n=8), LTP induced a 1.29 0.12 fold increase in fEPSP amplitude. In the presence of CXCL10, LTP induced a 2.04 0.20 fold increase of fEPSP amplitude, which was significantly higher than without CXCL10 (p=0.006). In slices from CXCR3 KO mice (n=9), there was no significant difference between fEPSP amplitudes with and without CXCL10 (1.77 0.15 versus 1.44 0.08, p=0.074). Conclusions: Presence of CXCL10 facilitates LTP in the hippocampus of WT mice, whereas it has no significant effect in transgenic mice with knocked-out CXCR3 receptor. Our results suggest that (1) the inflammatory cytokine CXCL10 enhances excitability and acitvity-dependent plasticity in the hippocampus, and that (2) this effect is mediated by its G-protein coupled receptor, CXCR3. CXCL10 may play a role in epileptogenicity associated with inflammatory conditions such as viral encephalitis.