An epitope specific patient-derived LGI1-autoantibody enhances neuronal excitability by modulating the Kv1.1 channel
Leucine-rich Glioma Inactivated protein 1 (LGI1) is expressed in the central nervous and genetic loss of function is associated with epileptic disorders. Also, patients with LGI1-directed autoantibodies have frequent focal seizures as a key feature of their disease. LGI1 is composed of a Leucine Rich Repeat (LRR) and an Epitempin (EPTP) domain. These domains are reported to interact with different aspects of the transsynaptic complex formed by LGI1 at excitatory synapses, including presynaptic
... v1 potassium channels. Patient-derived monoclonal antibodies (mAbs) are ideal reagents to study whether domain-specific LGI1-autoantibodies induce epileptiform activities in neurons, and their downstream mechanisms. To address this question, we measured the intrinsic excitability of CA3 pyramidal neurons in organotypic cultures from rat hippocampus treated with either a LRR- or an EPTP- reactive patient-derived mAb. The antibodies induced changes in neuronal intrinsic excitability which led us to measure their effects on Kv1-type potassium currents. We found an increase of intrinsic excitability correlated with a reduction of the sensitivity to a selective Kv1.1-channel blocker in neurons treated with the LRR mAb compared to the control, but not in neurons treated with the EPTP mAb. Our findings suggest LRR mAbs are able to modulate neuronal excitability that could account for epileptiform activities observed in patients.