Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission.
OBJECTIVE
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, α-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.
MRC Anatomical Neuropharmacology Unit, Oxford, UK.
Tatjana
T
Lalic
Philippa
P
Pettingill
Angela
A
Vincent
Marco
M
Capogna
D000818:Animals; D056654:CA3 Region, Hippocampal / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D020363:Limbic Encephalitis / Q000097:blood* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D019599:Mossy Fibers, Hippocampal / Q000502:physiology*; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology*
D007074:Immunoglobulin G