Abstracts

Rationale: The leucine-rich glioma inactivated gene 1 (LGI1) is the first gene found mutated in a human temporal lobe epilepsy (autosomal dominant lateral temporal lobe epilepsy, ADLTE). It is well-known that the perforant path provides the main excitatory input into the hippocampus and plays a critical role in the generation of temporal lobe seizures. Thus it is interesting to know whether the LGI1-encoded protein Lgi1 is involved in perforant path (PP) function. Methods: To investigate the functional involvement of Lgi1 in the PP-granule cell transmission, we have generated two transgenic mouse lines carrying copies of the full-length murine LGI1 gene in a bacterial artificial chromosome (BAC) vector: one carries a mutation in Lgi1 (835delC) found in ADLTE and the other over-expressing the wild-type Lgi1. We recorded glutamatergic synaptic currents using whole-cell patch-clamp of hippocampal dentate granule neurons in an acute brain slice preparation.Results: By recording the excitatory postsynaptic currents (EPSCs) in the dentate granule cells, we found that the evoked responses of stimulating the medial perforant path (MPP) are increased in the mutant Lgi1 mouse and decreased in the Lgi1 over-expressing mice. The paired pulse ratio of MPP-granule cell EPSCs is reduced in the mutant and enhanced in the over-expressing Lgi1 transgenic mice, indicating that Lgi1 has a modulatory effect on the presynaptic release probability. The results are consistent with the finding of increased and decreased miniature EPSC frequency in mutant Lgi1 and Lgi1 over-expressing mice compared to controls, respectively. The lower release probability of MPP-granule cell transmission in Lgi1 over-expressing mice can be reversed by incubating the hippocampal slice in the irreversible Kv1 channel blocker dendrotoxin. Furthermore, high frequency stimulation of MPP causes a transient increase in the paired pulse ratio in the wild-type animal, whereas no such a change is observed in the mutant Lgi1 mouse.Conclusions: These results identify Lgi1 as a novel synaptic terminal protein that functions to adjust presynaptic transmitter release of the perforant path. Excess excitatory inputs render the fusible effect of Lgi1 by lowering the presynaptic release probability.