Abstract
ObjectiveAutoantibody‐mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential.MethodsWe compared the effects of CSF containing leucine‐rich glioma inactivated 1 (LGI1), contactin‐associated protein‐like 2 (CASPR2), and γ‐aminobutyric acid receptor B (GABABR) antibodies on ex vivo electrophysiological parameters after stereotactic hippocampal inoculation into mice. Whole‐cell patch‐clamp and extracellular recordings from CA1 pyramidal neurons and CA3‐CA1 field recordings in ex vivo murine brain slices were used to study neuronal function.ResultsBy comparison to control CSF, AE CSFs increased the probability of glutamate release from CA3 neurons. In addition, LGI1‐ and CASPR2 antibodies containing CSFs induced epileptiform activity at a population level following Schaffer collateral stimulation. CASPR2 antibody containing CSF was also associated with higher spontaneous firing of CA1 pyramidal neurons. On the contrary, GABABR antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials.InterpretationUsing patient CSF, we have demonstrated that the AE‐associated antibodies against LGI1 and CASPR2 are able to increase hippocampal CA1 neuron excitability, facilitating epileptiform activity. These findings provide in vivo pathogenic insights into neuronal dysfunction in these conditions.
Highlights
Autoantibody-mediated encephalitis (AE) is a clinical syndrome with features including subacute memory impairment, neuropsychiatric symptoms, movement disorders, bilateral temporal lobe involvement on brain MRI, and epileptiform EEG abnormalities.[1]
Though the pyramidal neurons from mice injected with the other samples only showed occasional spontaneous action potential (AP) firing, the majority of neurons from mice injected with the contactin-associated proteinlike 2 (CASPR2) antibody CSF demonstrated modestly increased spontaneous AP activity (5/8 neurons; P = 0.049; Fig. 2C)
The first to use in vivo inoculation of CSF antibodies for neurophysiological ex vivo studies, we demonstrate that antibodies targeting leucine-rich glioma inactivated 1 (LGI1) and CASPR2 are able to boost glutamatergic transmission and increase epileptic activity of CA1 pyramidal neurons
Summary
Autoantibody-mediated encephalitis (AE) is a clinical syndrome with features including subacute memory impairment, neuropsychiatric symptoms, movement disorders, bilateral temporal lobe involvement on brain MRI, and epileptiform EEG abnormalities.[1]. While phenotypic associations with the individual autoantibodies are well-described,[2,3,4] distinct underlying molecular mechanisms and functional consequences are still uncertain.[5,6]. Internalization of glutamate receptors has been implicated in hippocampal dysfunction leading to seizures and cognitive impairment in glutamate receptor-related autoimmune encephalitis.[7,8] Frequent seizures and cognitive impairment are characteristic of leucine-rich glioma inactivated 1(LGI1), contactin-associated proteinlike 2 (CASPR2), and c-aminobutyric acid receptor B (GABABR) antibodies.[9,10,11,12] Only one study has systematically examined the functional effects of serum LGI1 antibodies on synaptic transmission and showed a facilitation in mossy fiber-CA3 synaptic transmission.[11] Another study reported increased neuronal excitability with CASPR2 antibodies, though not on central nervous system neurons.[13]
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