Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions

Abstract

Purpose: We present a case of voltage-gated potassium channel (VGKC) complex antibody-positive limbic encephalitis (LE) harboring autoantibodies against Kv1.2. Since the patient responded well to immunotherapy, the autoantibodies were regarded as pathogenic. We aimed to characterize the pathophysiological role of this antibody in comparison to an antibody against the VGKC-associated protein contactin-associated protein-2 (CASPR2). Methods: Stereotactic injection of patient sera (anti-Kv1.2-associated LE or anti-CASPR2 encephalopathy) and a control subject was performed into the hippocampus of the anesthetized rat in vivo, and hippocampal slices were prepared for electrophysiological purposes. Using extra-and intracellular techniques, synaptic transmission, long-term potentiation (LTP) and vulnerability to pro-epileptic conditions were analyzed. Results: We observed that the slope of the field excitatory postsynaptic potential (fEPSP) was significantly increased at Schaffer collateral-CA1 synapses in anti-Kv1.2treated and anti-CASPR2-treated rats, but not at medial perforant path-dentate gyrus synapses. The increase of the fEPSP slope in CA1 was accompanied by a decrease of the paired-pulse ratio in anti-Kv1.2, but not in anti-CASPR2 tissue, indicating presynaptic site of anti-Kv1.2. In addition, anti-Kv1.2 tissue showed enhanced LTP in CA1, but dentate gyrus LTP remained unaltered. Importantly, LTP in slices from anti-CASPR2-treated animals did not differ from control values. Intracellular recordings from CA1 neurons revealed that the resting membrane potential and a single action potential were not different between anti-Kv1.2 and control tissue. However, when the

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

“…The C-terminal and N-terminal cytosolic domains are less conserved and regulate tetramerization and the association to modifying subunits [ 9 , 10 ]. Several antibody-mediated neurological diseases in children and adults have been linked to proteins associated with K v 1 channel components, such as leucine-rich glioma-inactivated 1, contactin-associated protein 2, and particularly K v 1 channel subunits [ 11 , 12 ].…”

Molecular dissection of an immunodominant epitope in Kv1.2-exclusive autoimmunity

“…Among K v 1 complex-directed autoantibodies, anti-K v 1 are among the most prevalent (7, 8); compared with LGI1 and CASPAR2 autoantibodies subgroups, their association with clinical syndromes and their immunotherapy responsiveness, however, appears less clear. Despite the association of K v 1 subfamily autoantibodies to neurological autoimmune diseases (5,6,9) and their pathology (7,8,10,11,(20)(21)(22) and their resulting diagnostic and therapeutic potential the involved K v 1 epitopes remained largely undefined. Here, we provide a first K v 1.2 autoantibody epitope landscape within a cohort of 36 K v 1.2exclusive neuropsychiatric patients and 18 healthy controls.…”

“…The role of K v 1.2 in autoimmune disorders remains to be fully explored ( 20 ). K v 1.2 autoantibodies were shown to exacerbate an epileptic phenotype in rodent models ( 21 ), and cases of K v 1 autoantibody–associated limbic encephalitis were reported to be immunotherapy-sensitive ( 22 ). In vitro evidence suggests that autoantibodies can potentially reach their intracellular epitopes through Fc receptor–mediated internalization ( 23 , 24 ), consequently leading to a smoldering autoimmunity.…”

KCNA2 Autoimmunity in Progressive Cognitive Impairment: Case Series and Literature Review

“…The sera of both patients with previous anti-CASPR2 encephalopathy and those with anti-Kv1.2. antibodies altered the cellular excitability of hippocampal structures in the rat, and facilitated epileptic conditions, but through different pathomechanisms [ 36 ]. Their work attributes anti-Kv1.2 with a mode of action in patients with antibody-associated temporal lobe epilepsy in limbic encephalitis, and provides evidence that anti-Kv1.2 may bear pathogenetic potential.…”