Abstracts

Rationale: The medial septum, through theta rhythm generation, inhibits the appearance of interictal spikes and seizures observed in the hippocampus in epileptic animals from the pilocarpine model of Temporal Lobe Epilepsy (TLE). The antiepileptic effect of the theta functional state is probably produced by a common functional mechanism between abnormal synchronization (epileptic spikes) and normal synchronization (theta rhythm) or by increased hippocampal thresholds by septal inputs (for review see Colom & Garrido-Sanabria, 2007). In the pilocarpine model of TLE, Colom et al. (2006) and Garrido-Sanabria et al. (2006) have determined that medial septal (MS/DB) neurons increase their firing rates during chronic epilepsy and that the GABAergic neurons from both MS/DB and lateral septal regions are highly and selectively vulnerable to the epilepsy process. Septal GABAergic neurons exclusively inhibit hippocampal GABAergic interneurons (Freund and Antal, 1988). Thus, their destruction will disturb the hippocampal theta rhythm by increasing hippocampal inhibition, decoupling pyramidal cells thus promoting desynchronization and facilitating the development of abnormal islands of excitation. Methods: To investigate the exact role of the MS/DB GABAergic neurons in hippocampal theta rhythm generation and its antiepileptic role, the antibody gamma amino butyric acid transporter 1 (GAT1) conjugated to saporin (SAP) was injected (3 L, 5 L, and 6 L at 325ng/ L) in the MS/DB of adults Sprague Dawley rats. Subsequently, the effects of the septal GABAergic neuronal loss in hippocampal function were investigated by hippocampal EEG recordings from freely moving rats. Results: At 3 L, 5 L and 6 L injections, Population estimates of MS/DB neurons were analyzed using a stereological approach. A significant reduction (75%-90%; p<0.0001) in the MS/DB GABAergic population was observed. Glutamatergic and Cholinergic MS/DB neurons were only statistically significant at 6 L. In the freely moving rats, there was an observable decrease in theta amplitude (3 L; 20% and 5 L; 30%), but there was no significant difference in frequency or presence of abnormal activity in the EEG. Conclusions: The destruction of 70-80% of MS/DB GABAergic neurons produce a moderate reduction of theta amplitude (20-30%) and this disinhibition is not enough to induce spontaneous epileptic activity.