LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development.

Morgane Boillot,Nathalie Rouach,Eric Leguern,Chun-Yao Lee,Camille Allene,Stéphanie Baulac

doi:10.1038/srep21769

Abstract

The secreted leucine-rich glioma inactivated 1 (LGI1) protein is an important actor for human seizures of both genetic and autoimmune etiology: mutations in LGI1 cause inherited temporal lobe epilepsy, while LGI1 is involved in antibody-mediated encephalitis. Remarkably, Lgi1-deficient (Lgi1−/−) mice recapitulate the epileptic disorder and display early-onset spontaneous seizures. To understand how Lgi1-deficiency leads to seizures during postnatal development, we here investigated the early functional and structural defects occurring before seizure onset in Lgi1−/− mice. We found an increased excitatory synaptic transmission in hippocampal slices from Lgi1−/− mice. No structural alteration in the morphology of pyramidal cell dendrites and synapses was observed at this stage, indicating that Lgi1-deficiency is unlikely to trigger early developmental abnormalities. Consistent with the presynaptic subcellular localization of the protein, Lgi1-deficiency caused presynaptic defects, with no alteration in postsynaptic AMPA receptor activity in Lgi1−/− pyramidal cells before seizure onset. Presynaptic dysfunction led to increased synaptic glutamate levels, which were associated with hyperexcitable neuronal networks. Altogether, these data show that Lgi1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development. We therefore here reveal that increased presynaptic glutamate release is a key early event resulting from Lgi1-deficiency, which likely contributes to epileptogenesis.

Highlights

Detected at postnatal day 9 (P9), Lgi1− /− mice display frequent spontaneous epileptic seizures from P10, and die within the first three postnatal weeks[12]
To get insight into the pathogenic mechanisms induced by Lgi1-deficiency, we investigated whether, before seizure onset, glutamatergic synaptic transmission is already affected in Lgi1deficient mice
Analysis of AMPAR miniature excitatory postsynaptic currents from CA1 pyramidal cells revealed in P8 Lgi1− /− mice a significant increase in amplitude of these events (Lgi1− /−, n = 20; Lgi1+ /+, n = 18; p < 0.05, t-test; Fig. 1a,d)

Summary

Introduction

Detected at postnatal day 9 (P9), Lgi1− /− mice display frequent spontaneous epileptic seizures from P10, and die within the first three postnatal weeks[12]. Electrophysiological recordings from hippocampal slices of Lgi1− /− mice suggested a role for Lgi[1] in controlling transmission at excitatory synapses. Because of contradictory results, it remains unclear whether Lgi[1] promotes or reduces excitatory synaptic transmission, and whether it acts pre or postsynaptically[13,14]. We searched for possible structural and functional defects in hippocampal slices from Lgi1− /− mice at early postnatal stages (P8– P9), when no seizures are detected. At this stage, no morphological rearrangements at both synaptic and dendritic levels were evident in Lgi1− /− mice. Synaptic excitatory transmission was enhanced, independently of any postsynaptic effect. The increased glutamatergic synaptic transmission resulted from a presynaptic defect, which induced enhanced synaptic glutamate levels, and was associated with hippocampal network hyperexcitability

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