Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission

Abstract

SUMMARYPurpose: Limbic encephalitis (LE) is a central nervous system (CNS) disease characterized by subacute onset of memory loss and epileptic seizures. A well-recognized form of LE is associated with voltage-gated potassium channel complex antibodies (VGKC-Abs) in the patients' sera. We aimed to test the hypothesis that purified immunoglobulin G (IgG) from a VGKC-Ab LE serum would excite hippocampal CA3 pyramidal cells by reducing VGKC function at mossy-fiber (MF)-CA3 pyramidal cell synapses. Methods: We compared the effects of LE and healthy control IgG by whole-cell patch-clamp and extracellular recordings from CA3 pyramidal cells of rat hippocampal acute slices. Results: We found that the LE IgG induced epileptiform activity at a population level, since synaptic stimulation elicited multiple population spikes extracellularly recorded in the CA3 area. Moreover, the LE IgG increased the rate of tonic firing and strengthened the MF-evoked synaptic responses. The synaptic failure of evoked excitatory postsynaptic currents (EPSCs) was significantly lower in the presence of the LE IgG compared to the control IgG. This suggests that the LE IgG increased the release probability on MF-CA3 pyramidal cell synapses compared to the control IgG. Interestingly, a-dendrotoxin (120 nM), a selective Kv1.1, 1.2, and 1.6 subunit antagonist of VGKC, mimicked the LE IgG-mediated effects. Conclusions: This is the first functional demonstration that LE IgGs reduce VGKC function at CNS synapses and increase cell excitability.

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

“…Do our present findings have implications for LE with LGI1 autoimmunity? Lalic et al (29) have reported that in vitro application of serum from LE patients increased the release probability at mossy-fiber CA3 cell synapses, and this effect was mimicked by DTX. It will be interesting to determine whether the anti-LGI1 autoantibodies identified in LE patients have an impact on Kv1-channel expression.…”

Neuroinflammation: Ways in Which the Immune System Affects the Brain

“…Purified IgG from a patient with LGI1 increased neuronal excitability in hippocampal slices in a similar way to the snake toxin α-dendrotoxin, suggesting the antibodies act to reduce Kv1.1, 1. 2 and/or 1.6 function and are epileptogenic [54].…”

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

“…As LGI1 is almost exclusively expressed in central nervous system neurons, and CASPR2 in both the central and peripheral nervous systems, the antibodies are considered likely mediators of the diseases. While careful correlations between antibody levels and clinical outcomes in individual patients, in combination with passive transfer experiments in animals, are required to formally assess VGKC-complex antibody pathogenicity, it has been proven that LGI1-antibodies can generate seizure activity in hippocampal slice cultures 16 . Interestingly, further evidence for the disease relevance of these proteins come from known genetic variations.…”