Human CASPR2 antibodies reversibly alter memory and the CASPR2 protein complex

Abstract

Objective The encephalitis associated with antibodies against contactin-associated protein-like 2 (CASPR2) is presumably antibody-mediated but the antibody effects and whether they cause behavioral alterations are not well-known. Here, we used a mouse model of patients’ IgG transfer and super-resolution microscopy to demonstrate the antibody pathogenicity.

Methods IgG from patients with anti-CASPR2 encephalitis or healthy controls were infused into the cerebroventricular system of mice. The levels and colocalization of CASPR2 with transient axonal glycoprotein-1 (TAG1) were determined with Stimulated Emission Depletion (STED) microscopy (40-70μm lateral resolution). Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKC) and GluA1-containing AMPA receptors were quantified with confocal microscopy. Behavioral alterations were assessed with standard behavioral paradigms. Cultured neurons were used to determine the levels of intracellular CASPR2 and TAG1 after exposure to patients’ IgG.

Results Infusion of patients’ IgG, but not control IgG, caused memory impairment along with hippocampal reduction of surface CASPR2 clusters and decreased CASPR2/TAG1 colocalization. In cultured neurons, patients’ IgG led to an increase of intracellular CASPR2 without affecting TAG1, suggesting selective CASPR2 internalization. Additionally, mice infused with patients’ IgG showed decreased levels of Kv1.1 and GluA1 (two CASPR2 regulated proteins). All these alterations and the memory deficit reverted to normal after removing patients’ IgG.

Interpretation IgG from patients with anti-CASPR2 encephalitis cause reversible memory impairment, inhibit the interaction of CASPR2/TAG1, and decrease the levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the postulates of antibody-mediated disease and provide a biological basis for antibody-removing treatment approaches.