Hippocampal epileptogenesis in autoimmune encephalitis.

Abstract

OBJECTIVE:

Autoantibody-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.

METHODS:

We compared the effects of CSF containing leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and γ-aminobutyric acid receptor B (GABAB R) 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.

RESULTS:

By 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, GABAB R antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials.

INTERPRETATION:

Using 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.

• Authors: Michele Romoli, Paraskevi Krashia, Arjune Sen, Diego Franciotta, Matteo Gastaldi, Annalisa Nobili, Andrea Mancini, Elena Nardi Cesarini, Pasquale Nigro, Nicola Tambasco, Nicola B Mercuri, Lucilla Parnetti, Massimiliano Di Filippo, Marcello D'Amelio, Sarosh R Irani, Cinzia Costa, Paolo Calabresi
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 6 Issue 11 Pg. 2261-2269 (11 2019) ISSN: 2328-9503 [Electronic] United States
• PMID: 31617317 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Chemical References

• Autoantibodies
• Autoantigens
• CNTNAP2 protein, human
• Intracellular Signaling Peptides and Proteins
• LGI1 protein, human
• Membrane Proteins
• Nerve Tissue Proteins
• Receptors, GABA-B

Topics

• Animals
• Autoantibodies (cerebrospinal fluid, pharmacology)
• Autoantigens (immunology)
• Autoimmune Diseases of the Nervous System (complications, immunology)
• Encephalitis (complications, immunology)
• Epilepsy (etiology, immunology)
• Hippocampus (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (immunology)
• Male
• Membrane Proteins (immunology)
• Mice
• Mice, Inbred C57BL
• Nerve Tissue Proteins (immunology)
• Neurons (drug effects)
• Receptors, GABA-B (immunology)