Abstracts

Rationale: Inflammation is a known factor in the generation and modulation of epileptic seizures as well as seizure-related neurotoxicity. We have demonstrated that peripheral inflammation is capable of increasing susceptibility to experimental in-vivo and in-vitro seizures through immune signaling that includes microglial cell activation and cytokine release in the brain. However, the neuronal correlates of this increased excitability are not clear.Methods: We used a rat model of inflammatory colitis, in which colon inflammation was induced by single-dose administration of trinitrobenzenesulfonic acid (TNBS) per rectum. At the height of inflammation (4 days after TNBS treatment), we obtained acute hippocampus slices and performed field-potential and patch-clamp recordings from the CA1 area. We studied the changes in synaptic transmission and AMPA and NMDA receptor composition and function. Results: We observed enhanced evoked field-potentials in inflamed animals with no change in paired-pulse ratio, indicating a possible enhanced post-synaptic AMPA receptor-mediated response. In pyramidal neurons from the animals with colon inflammation, voltage clamp recordings revealed a decrease in AMPA/NMDA ratio, when compared with control animals (p<0.001, n=15 (TNBS), 16 (control)). When studying the AMPA receptor currents, we found an increase in the amplitude (p<0.05, n=8 (TNBS), 7 (control)), but not frequency of AMPA-receptor mediated miniature currents. Moreover, the evoked currents showed inward rectification at positive holding potentials, indicating a switch to GluR2-lacking AMPA receptors. This was confirmed by observing a greater reduction in the AMPA-receptor mediated excitatory postsynaptic current (EPSC) amplitude after applying Naspm trihydrochloride, an antagonist of the GluR2-lacking AMPA receptors (p<0.01, n=8 (TNBS), 7 (control)). There was also a reduced NR2b-containing NMDA receptor-mediated neurotransmission, evident through decreased effect of specific NR2b-containing NMDA antagonist (Ro25-6981) on evoked NMDA mediated EPSCs (p<0.01, n=9 (TNBS), 10 (control)).Conclusions: Our data present an enhanced hippocampal gluatamatergic synaptic transmission accompanied by subunit changes of both AMPA and NMDA receptors in the pyramidal neurons of CA1 area during peripheral inflammation. These might in part explain the increased central excitability associated with peripheral inflammatory events.