TY - JOUR
T1 - Hippocampal epileptogenesis in autoimmune encephalitis
AU - Romoli, Michele
AU - Krashia, Paraskevi
AU - Sen, Arjune
AU - Franciotta, Diego
AU - Gastaldi, Matteo
AU - Nobili, Annalisa
AU - Mancini, Andrea
AU - Nardi Cesarini, Elena
AU - Nigro, Pasquale
AU - Tambasco, Nicola
AU - Mercuri, Nicola B.
AU - Parnetti, Lucilla
AU - Di Filippo, Massimiliano
AU - D’Amelio, Marcello
AU - Irani, Sarosh R.
AU - Costa, Cinzia
AU - Calabresi, Paolo
PY - 2019
Y1 - 2019
N2 - 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 (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. 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, GABABR 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.
AB - 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 (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. 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, GABABR 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.
KW - autoimmune encephalitis
KW - neurological disorders
KW - autoimmune encephalitis
KW - neurological disorders
UR - http://hdl.handle.net/10807/150409
U2 - 10.1002/acn3.50919
DO - 10.1002/acn3.50919
M3 - Article
SN - 2328-9503
VL - 6
SP - 2261
EP - 2269
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
ER -