Abstracts

Rationale: Basal forebrain septal nuclei provide the main cholinergic innervation to the hippocampus, and play a critical role in modulating hippocampal excitability. In animal models of epilepsy, destruction of septal cholinergic neurons facilitates seizures and epileptogenesis (e.g. Ferencz et al, Neuroscience 2001; Silveira et al, Dev. Brain Res. 2002), while septal stimulation is antiepileptic (e.g. Colom et al, J Neurophys. 2006; Miller et al, Epil. Res. 1994). Septal nuclei have received little study in human TLE. Methods: Septal volume was measured in patients with pharmacoresistant temporal lobe epilepsy (TLE; n=24), extratemporal epilepsy (ETE; n=23) and controls (n=89) using MRI and recently-developed probabilistic maps of human septal nuclei (Zaborszky et al, Neuroimage 2008.) To confirm results, an independent dataset consisting of 20 TLE patients and 25 controls was also analyzed. Expression of the high affinity choline transporter (HACT), a marker for septal cholinergic nerve terminals, was assessed in surgical specimens from patients who had undergone temporal lobectomy for intractable TLE and autopsy controls (n=5/group) by immunocytochemistry and Western blot analysis. Results: Patients with TLE had significantly larger bilateral septal nuclei than patients with ETE and controls (p<0.05). Patients with TLE demonstrated HACT upregulation in the hippocampus (204±9% of control), but not in the temporal cortex (38±49% of control). Increased HACT expression was mostly observed in the in the molecular layer of the dentate gyrus. Conclusions: These results demonstrate augmentation of the septo-hippocampal cholinergic system in patients with pharmacoresistant TLE. Similar results have been demonstrated in an animal model of TLE (Holtzman et al. J. Neurosci., 1995). We interpret septal enlargement in TLE as MR-detectable evidence of plasticity/augmentation of the normally-antiepileptic cholinergic septo-hippocampal system. Further investigation of this system could be relevant to development of new therapies such as septal stimulation for refractory TLE.