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000164003 0247_ $$2doi$$a10.1523/JNEUROSCI.1689-21.2022
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000164003 1001_ $$0P:(DE-2719)2811708$$aAndrzejak, Ewa Izabella$$b0$$eFirst author$$udzne
000164003 245__ $$aPatient-Derived Anti-NMDAR Antibody Disinhibits Cortical Neuronal Networks through Dysfunction of Inhibitory Neuron Output.
000164003 260__ $$aWashington, DC$$bSoc.$$c2022
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000164003 520__ $$aAnti-NMDA receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder associated with autoantibodies against NMDARs, which cause a variety of symptoms from prominent psychiatric and cognitive manifestations to seizures and autonomic instability. Previous studies mainly focused on hippocampal effects of these autoantibodies, helping to explain mechanistic causes for cognitive impairment. However, antibodies' effects on higher cortical network function, where they could contribute to psychosis and/or seizures, have not been explored in detail until now. Here, we employed a patient-derived monoclonal antibody targeting the NR1 subunit of NMDAR and tested its effects on in vitro cultures of rodent cortical neurons, using imaging and electrophysiological techniques. We report that this hNR1 antibody drives cortical networks to a hyperexcitable state and disrupts mechanisms stabilizing network activity such as Npas4 signaling. Network hyperactivity is in part a result of a reduced synaptic output of inhibitory neurons, as indicated by a decreased inhibitory drive and levels of presynaptic inhibitory proteins, specifically in inhibitory-to-excitatory neuron synapses. Importantly, on a single-cell level hNR1 antibody selectively impairs NMDAR-mediated currents and synaptic transmission of cortical inhibitory neurons, yet has no effect on excitatory neurons, which contrasts with its effects on hippocampal neurons. Together, these findings provide a novel, cortex-specific mechanism of antibody-induced neuronal hyperexcitability, highlighting regional specificity underlying the pathology of autoimmune encephalitis.SIGNIFICANCE STATEMENT It is increasingly appreciated that the inadvertent activation of the immune system within CNS can underlie pathogenesis of neuropsychiatric disorders. Although the exact mechanisms remain elusive, autoantibodies derived from patients with autoimmune encephalitis pose a unique tool to study pathogenesis of neuropsychiatric states. Our analysis reveals that autoantibody against the NMDA receptor (NMDAR) has a distinct mechanism of action in the cortex, where it impairs function of inhibitory neurons leading to increased cortical network excitability, in contrast to previously described hippocampal synaptic mechanisms of information encoding, highlighting brain regional specificity. Notably, similar mechanism of NMDAR-mediated inhibitory hypofunction leading to cortical disinhibition has been suggested to underlie pathology of schizophrenia, hence our data provide new evidence for common mechanisms underlying neuropsychiatric disorders.
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000164003 542__ $$2Crossref$$i2022-10-13$$uhttps://creativecommons.org/licenses/by-nc-sa/4.0/
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000164003 650_7 $$2Other$$aNMDAR
000164003 650_7 $$2Other$$aautoantibodies
000164003 650_7 $$2Other$$aautoimmune encephalitis
000164003 650_7 $$2Other$$acortical interneurons
000164003 650_7 $$2Other$$anetwork excitability
000164003 650_7 $$2NLM Chemicals$$aAutoantibodies
000164003 650_7 $$2NLM Chemicals$$aReceptors, N-Methyl-D-Aspartate
000164003 650_2 $$2MeSH$$aAutoantibodies: metabolism
000164003 650_2 $$2MeSH$$aEncephalitis
000164003 650_2 $$2MeSH$$aHashimoto Disease
000164003 650_2 $$2MeSH$$aHumans
000164003 650_2 $$2MeSH$$aNeurons: physiology
000164003 650_2 $$2MeSH$$aReceptors, N-Methyl-D-Aspartate: metabolism
000164003 650_2 $$2MeSH$$aSeizures: metabolism
000164003 7001_ $$aRabinovitch, Eshed$$b1
000164003 7001_ $$0P:(DE-2719)2811468$$aKreye, Jakob$$b2$$udzne
000164003 7001_ $$0P:(DE-2719)2810931$$aPrüss, Harald$$b3$$udzne
000164003 7001_ $$00000-0002-3905-2444$$aRosenmund, Christian$$b4
000164003 7001_ $$00000-0001-9197-326X$$aZiv, Noam E$$b5
000164003 7001_ $$0P:(DE-2719)2810922$$aGarner, Craig Curtis$$b6$$udzne
000164003 7001_ $$0P:(DE-2719)2810967$$aAckermann, Frauke$$b7$$eLast author$$udzne
000164003 77318 $$2Crossref$$3journal-article$$a10.1523/jneurosci.1689-21.2022$$bSociety for Neuroscience$$d2022-03-03$$n15$$p3253-3270$$tThe Journal of Neuroscience$$v42$$x0270-6474$$y2022
000164003 773__ $$0PERI:(DE-600)1475274-8$$a10.1523/JNEUROSCI.1689-21.2022$$gVol. 42, no. 15, p. 3253 - 3270$$n15$$p3253-3270$$tThe journal of neuroscience$$v42$$x0270-6474$$y2022
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