Autoantibodies against LGI1 cause limbic encephalitis with characteristic focal epileptic seizures and memory disorders. LGI1 is secreted by neurons and consists of two functional domains: a leucine-rich (LRR) and an epitempin (EPTP) region and forms complexes in synapses and axons via the receptors ADAM22/23 with Kv1 potassium channels and structural proteins such as PSD95 and glutamate receptors, whereby LGI1 can exert an influence on synaptic transmission and intrinsic excitability. To understand changes in neuronal function by LGI1 encephalitis, we used patients’ serum IgGs or monoclonal antibodies with specific reactivity against the LRR or EPTP domain. We investigated the effect of LGI1 antibodies on synaptic function and their role in neuronal excitability using electrophysiological approaches and super-resolution imaging.LGI1-IgGs increased presynaptic excitatory glutamate release and enhanced action potential broadening. This is mainly due to a disturbed function of Kv1 channels. When domain-specific antibodies were examined, these observations were only seen with EPTP- but not LRR-specific IgGs. In addition, we found an increased intrinsic excitability, measured by the number of action potentials and the firing rate. This effect is also due to reduced Kv1 conductance, but at the axon initial segment, as supported by electrophysiological data and a biophysical network model. This effect was predominantly found with LRR-specific IgGs.Our studies show that autoantibodies impair the important interaction of LGI1 and potassium channels at the axon initial segment and in the synapse. The increased excitability could be responsible for the development of epileptic seizures and impaired memory formation.