Pathomechanisms of autoantibody-induced autoimmunity to AMPA receptors

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Recently, several potentially pathogenic antibodies (AB) against neuronal ionotropic receptors (e.g. AMPA and NMDA receptors) have been described in patients with limbic encephalitis. If these AB contribute directly to disease pathogenesis and how they might induce typical disease symptoms, e.g. cognitive deficits, impaired memory, seizures, or changes in personality has not been demonstrated to date. Here, we will investigate the impact of various purified patient IgG preparations with AB to the AMPA receptor on synaptic transmission. The functional relevant GluR2 subunit of the AMPA-receptor has been identified to be the specific target epitope of the human auto-AB. Using super-resolution dSTORM microscopy we aim to investigate changes in synaptic expression and localisation of AMPA-receptor subunits. We will use patch-clamp recordings of dissociated neurons after stimulation of individual synaptic boutons to investigate AB-mediated effects on synaptic transmission. These patch-clamp recordings will be correlated with dSTORM analysis of the respective receptor fields. Effects on quantal parameters of synaptic transmission and on short- and long-term plasticity will be tested in acute hippocampal slices. AB-induced alterations of learning and memory will be investigated after stereotactic intracerebral application of patient-IgG fractions in mice. Histologically, we will evaluate receptor density and changes in synaptic architecture. These experiments aim to elucidate the underlying pathophysiology of limbic encephalitis with AB against AMPA-receptors. In terms of basic science, this project might provide new insights into autoimmune-mediated dysfunctions of the AMPA receptor GluR2 subunit. From the clinical view, evidence of AB-mediated pathophysiology could serve as a proof of principle example in this spectrum disorder and would have direct implications on the therapeutic strategy treating patients suffering from limbic encephalitis.