LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.
Brain. 2018-10-20; :
DOI: 10.1093/brain/awy253
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Petit-Pedrol M(1), Sell J(2), Planagumà J(1), Mannara F(1), Radosevic M(1), Haselmann H(2)(3), Ceanga M(2), Sabater L(1), Spatola M(1)(4), Soto D(1)(5), Gasull X(1)(5), Dalmau J(1)(6)(7)(8), Geis C(2)(3).
Author information:
(1)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, Barcelona, Spain.
(2)Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany.
(3)Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena,
Germany.
(4)University of Lausanne (UNIL), Lausanne, Switzerland.
(5)Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de
Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de
Barcelona, Barcelona, Spain.
(6)Department of Neurology, University of Pennsylvania, Philadelphia, USA.
(7)Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER),
Valencia, Spain.
(8)Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Comment in
Brain. 2018 Nov 1;141(11):3092-3095.
Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that
forms a trans-synaptic complex that includes the presynaptic disintegrin and
metalloproteinase domain-containing protein 23 (ADAM23), which interacts with
voltage-gated potassium channels Kv1.1, and the postsynaptic ADAM22, which
interacts with AMPA receptors. Human autoantibodies against LGI1 associate with a
form of autoimmune limbic encephalitis characterized by severe but treatable
memory impairment and frequent faciobrachial dystonic seizures. Although there is
evidence that this disease is immune-mediated, the underlying LGI1
antibody-mediated mechanisms are unknown. Here, we used patient-derived
immunoglobulin G (IgG) antibodies to determine the main epitope regions of LGI1
and whether the antibodies disrupt the interaction of LGI1 with ADAM23 and
ADAM22. In addition, we assessed the effects of patient-derived antibodies on
Kv1.1, AMPA receptors, and memory in a mouse model based on cerebroventricular
transfer of patient-derived IgG. We found that IgG from all patients (n = 25),
but not from healthy participants (n = 20), prevented the binding of LGI1 to
ADAM23 and ADAM22. Using full-length LGI1, LGI3, and LGI1 constructs containing
the LRR1 domain (EPTP1-deleted) or EPTP1 domain (LRR3-EPTP1), IgG from all
patients reacted with epitope regions contained in the LRR1 and EPTP1 domains.
Confocal analysis of hippocampal slices of mice infused with pooled IgG from
eight patients, but not pooled IgG from controls, showed a decrease of total and
synaptic levels of Kv1.1 and AMPA receptors. The effects on Kv1.1 preceded those
involving the AMPA receptors. In acute slice preparations of hippocampus,
patch-clamp analysis from dentate gyrus granule cells and CA1 pyramidal neurons
showed neuronal hyperexcitability with increased glutamatergic transmission,
higher presynaptic release probability, and reduced synaptic failure rate upon
minimal stimulation, all likely caused by the decreased expression of Kv1.1.
Analysis of synaptic plasticity by recording field potentials in the CA1 region
of the hippocampus showed a severe impairment of long-term potentiation. This
defect in synaptic plasticity was independent from Kv1 blockade and was possibly
mediated by ineffective recruitment of postsynaptic AMPA receptors. In parallel
with these findings, mice infused with patient-derived IgG showed severe memory
deficits in the novel object recognition test that progressively improved after
stopping the infusion of patient-derived IgG. Different from genetic models of
LGI1 deficiency, we did not observe aberrant dendritic sprouting or defective
synaptic pruning as potential cause of the symptoms. Overall, these findings
demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1
signalling, causing neuronal hyperexcitability, decreased plasticity, and
reversible memory deficits.