Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

Wright, Sukhvir; Rosch, Richard; Wilson, Max A; Upadhya, Manoj A.; Dhangar, Divya R; Clarke-Bland, Charlie; Wahid, Tamara T; Barman, Sumanta; Goebels, Norbert; Kreye, Jakob; Prüß, Harald; Jacobson, Leslie; Bassett, Danielle S.; Vincent, Angela; Greenhill, Stuart; Woodhall, Gavin L.

doi:10.1038/s42003-021-02635-8

Cited by 22 publications

(25 citation statements)

References 90 publications

(117 reference statements)

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“…Similar findings with increases in the theta and delta powers were detected in the kainate-induced status epilepticus in mice [ 32 ]. A recent study demonstrated that the intracerebroventricular injection of NMDAR Abs in rats led to a higher number of interictal events in the CA3 hippocampal region compared with the CA1, and to a spontaneous epileptic activity, highest in the CA3 region [ 33 ]. Additionally, whole-cell patch-clamp recordings from hippocampal CA3 pyramidal cells after the injection of NMDAR Abs showed a reduction in excitatory, but not in inhibitory, synaptic neurotransmission, or intrinsic hyperexcitability.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, whole-cell patch-clamp recordings from hippocampal CA3 pyramidal cells after the injection of NMDAR Abs showed a reduction in excitatory, but not in inhibitory, synaptic neurotransmission, or intrinsic hyperexcitability. The reduced synaptic excitatory neurotransmission is assumed to underlay seizures in this rat model of NMDAR Ab-mediated encephalitis [ 33 ]. In our study, GABA A R Abs led to decreased number and amplitude of sIPSCs in CA3 pyramidal neurons, the injection of NMDAR Abs caused no changes in the frequency or amplitude of sIPSCS.…”

Section: Discussionmentioning

confidence: 99%

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GABAA Receptor Autoantibodies Decrease GABAergic Synaptic Transmission in the Hippocampal CA3 Network

Menke

Ismail

Dornmair

et al. 2022

IJMS

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Autoimmune encephalitis associated with antibodies (Abs) against α1, β3, and γ2 subunits of γ-aminobutyric acid receptor A (GABAAR) represents a severe form of encephalitis with refractory seizures and status epilepticus. Reduction in inhibitory GABAergic synaptic activity is linked to dysfunction of neuronal networks, hyperexcitability, and seizures. The aim in this study was to investigate the direct pathogenic effect of a recombinant GABAAR autoantibody (rAb-IP2), derived from the cerebrospinal fluid (CSF) of a patient with autoimmune GABAAR encephalitis, on hippocampal CA1 and CA3 networks. Acute brain slices from C57BL/6 mice were incubated with rAb-IP2. The spontaneous synaptic GABAergic transmission was measured using electrophysiological recordings in voltage-clamp mode. The GABAAR autoantibody rAb-IP2 reduced inhibitory postsynaptic signaling in the hippocampal CA1 pyramidal neurons with regard to the number of spontaneous inhibitory postsynaptic currents (sIPSCs) but did not affect their amplitude. In the hippocampal CA3 network, decreased number and amplitude of sIPSCs were detected, leading to decreased GABAergic synaptic transmission. Immunohistochemical staining confirmed the rAb-IP2 bound to hippocampal tissue. These findings suggest that GABAAR autoantibodies exert direct functional effects on both hippocampal CA1 and CA3 pyramidal neurons and play a crucial role in seizure generation in GABAAR autoimmune encephalitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GABAA Receptor Autoantibodies Decrease GABAergic Synaptic Transmission in the Hippocampal CA3 Network

Menke

Ismail

Dornmair

et al. 2022

IJMS

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“…These in vitro models show how NMDAR modulation can prevent anti-NMDA encephalitis' pathogenic antibody effects such as seizures and treat them once established. 79 Further work on identifying patients at risks of seizures, and potential novel treatment options are important as we move forward in manging encephalitis.…”

Section: Managementmentioning

confidence: 99%

Encephalitis: diagnosis, management and recent advances in the field of encephalitides

Alam

Easton

Nicholson

et al. 2022

Postgraduate Medical Journal

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Encephalitis describes inflammation of the brain parenchyma, typically caused by either an infectious agent or through an autoimmune process which may be postinfectious, paraneoplastic or idiopathic. Patients can present with a combination of fever, alterations in behaviour, personality, cognition and consciousness. They may also exhibit focal neurological deficits, seizures, movement disorders and/or autonomic instability. However, it can sometimes present non-specifically, and this combined with its many causes make it a difficult to manage neurological syndrome. Despite improved treatments in some forms of encephalitides, encephalitis remains a global concern due to its high mortality and morbidity. Prompt diagnosis and administration of specific and supportive management options can lead to better outcomes. Over the last decade, research in encephalitis has led to marked developments in the understanding, diagnosis and management of encephalitis. In parallel, the number of autoimmune encephalitis syndromes has rapidly expanded and clinically characteristic syndromes in association with pathogenic autoantibodies have been defined. By focusing on findings presented at the Encephalitis Society’s conference in December 2021, this article reviews the causes, clinical manifestations and management of encephalitis and integrate recent advances and challenges of research into encephalitis.

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“…Reductions in excitatory neurotransmission caused by NMDAR antibodies in an vitro rat model may play a role in NMDA encephalitis [ 90 ]. These mechanisms invariably result in a state of excitatory and inhibitory chemical imbalance contributing to seizures in a significant number of patients.…”

Section: Nmdar Alterations and Their Role In Human Epilepsymentioning

confidence: 99%

Targeting NMDA Receptor Complex in Management of Epilepsy

2022

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N-methyl-D-aspartate receptors (NMDARs) are widely distributed in the central nervous system (CNS) and play critical roles in neuronal excitability in the CNS. Both clinical and preclinical studies have revealed that the abnormal expression or function of these receptors can underlie the pathophysiology of seizure disorders and epilepsy. Accordingly, NMDAR modulators have been shown to exert anticonvulsive effects in various preclinical models of seizures, as well as in patients with epilepsy. In this review, we provide an update on the pathologic role of NMDARs in epilepsy and an overview of the NMDAR antagonists that have been evaluated as anticonvulsive agents in clinical studies, as well as in preclinical seizure models.

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Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

Cited by 22 publications

References 90 publications

GABAA Receptor Autoantibodies Decrease GABAergic Synaptic Transmission in the Hippocampal CA3 Network

GABAA Receptor Autoantibodies Decrease GABAergic Synaptic Transmission in the Hippocampal CA3 Network

Encephalitis: diagnosis, management and recent advances in the field of encephalitides

Targeting NMDA Receptor Complex in Management of Epilepsy

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