Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

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Abstract

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.

Abstract

Stein, Barbosa et al. show that anti-NMDAR encephalitis and schizophrenia are characterized by reduced serial dependence in spatial working memory. Cortical network simulations show that this can be parsimoniously explained by a reduction in NMDAR-dependent short-term synaptic potentiation in these diseases.

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Most cited references 59

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Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex.

S Funahashi, C Bruce, P Goldman-Rakic (1989)

1. An oculomotor delayed-response task was used to examine the spatial memory functions of neurons in primate prefrontal cortex. Monkeys were trained to fixate a central spot during a brief presentation (0.5 s) of a peripheral cue and throughout a subsequent delay period (1-6 s), and then, upon the extinction of the fixation target, to make a saccadic eye movement to where the cue had been presented. Cues were usually presented in one of eight different locations separated by 45 degrees. This task thus requires monkeys to direct their gaze to the location of a remembered visual cue, controls the retinal coordinates of the visual cues, controls the monkey's oculomotor behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses. 2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding the principal sulcus (PS) while monkeys performed this task. An additional 31 neurons in the frontal eye fields (FEF) region within and near the anterior bank of the arcuate sulcus were also studied. 3. Of the 288 PS neurons, 170 exhibited task-related activity during at least one phase of this task and, of these, 87 showed significant excitation or inhibition of activity during the delay period relative to activity during the intertrial interval. 4. Delay period activity was classified as directional for 79% of these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions and were weak or absent for other cue directions. The remaining 21% were omnidirectional, i.e., showed comparable delay period activity for all visual field locations tested. Directional preferences, or lack thereof, were maintained across different delay intervals (1-6 s). 5. For 50 of the 87 PS neurons, activity during the delay period was significantly elevated above the neuron's spontaneous rate for at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with excitatory delay period activity were directional and few (8%) were omnidirectional. Most (62%) neurons with purely inhibitory delay period activity were directional, but a substantial minority (38%) was omnidirectional. 6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity for other cue directions. These inhibitory responses were usually strongest for, or centered about, cue directions roughly opposite those optimal for excitatory responses.(ABSTRACT TRUNCATED AT 400 WORDS)

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Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.

Ethan Hughes, Xiaoyu Peng, Amy Gleichman … (2010)

We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar to those obtained with models of genetic or pharmacologic attenuation of NMDAR function. Here, we demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization that correlates with patients' antibody titers. The mechanism of this decrease is selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments prepared from patients' antibodies did not decrease surface receptor density, but subsequent cross-linking with anti-Fab antibodies recapitulated the decrease caused by intact patient NMDAR antibodies. Moreover, whole-cell patch-clamp recordings of miniature EPSCs in cultured rat hippocampal neurons showed that patients' antibodies specifically decreased synaptic NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast to these profound effects on NMDARs, patients' antibodies did not alter the localization or expression of other glutamate receptors or synaptic proteins, number of synapses, dendritic spines, dendritic complexity, or cell survival. In addition, NMDAR density was dramatically reduced in the hippocampus of female Lewis rats infused with patients' antibodies, similar to the decrease observed in the hippocampus of autopsied patients. These studies establish the cellular mechanisms through which antibodies of patients with anti-NMDAR encephalitis cause a specific, titer-dependent, and reversible loss of NMDARs. The loss of this subtype of glutamate receptors eliminates NMDAR-mediated synaptic function, resulting in the learning, memory, and other behavioral deficits observed in patients with anti-NMDAR encephalitis.

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Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model.

A Compte, N Brunel, P Goldman-Rakic … (2000)

Single-neuron recordings from behaving primates have established a link between working memory processes and information-specific neuronal persistent activity in the prefrontal cortex. Using a network model endowed with a columnar architecture and based on the physiological properties of cortical neurons and synapses, we have examined the synaptic mechanisms of selective persistent activity underlying spatial working memory in the prefrontal cortex. Our model reproduces the phenomenology of the oculomotor delayed-response experiment of Funahashi et al. (S. Funahashi, C.J. Bruce and P.S. Goldman-Rakic, Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 61:331-349, 1989). To observe stable spontaneous and persistent activity, we find that recurrent synaptic excitation should be primarily mediated by NMDA receptors, and that overall recurrent synaptic interactions should be dominated by inhibition. Isodirectional tuning of adjacent pyramidal cells and interneurons can be accounted for by a structured pyramid-to-interneuron connectivity. Robust memory storage against random drift of the tuned persistent activity and against distractors (intervening stimuli during the delay period) may be enhanced by neuromodulation of recurrent synapses. Experimentally testable predictions concerning the neural basis of working memory are discussed.

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Author and article information

Contributors

Albert Compte:

ORCID: http://orcid.org/0000-0001-6594-6946

acompte@clinic.cat

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 25 August 2020

Publication date PMC-release: 25 August 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 4250

Affiliations

[1 ]GRID grid.10403.36, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), ; Carrer Rosselló 149, 08036 Barcelona, Spain

[2 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, CIBERSAM, Institute Clinic of Neurosciences, , Hospital Clínic, ; Carrer Villarroel 170, 08036 Barcelona, Spain

[3 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Service of Neurology, , Hospital Clínic, ; Carrer Villarroel 170, 08036 Barcelona, Spain

[4 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Department of Medicine, , University of Barcelona, ; Carrer Casanova 143, 08036 Barcelona, Spain

[5 ]GRID grid.425902.8, ISNI 0000 0000 9601 989X, Institució Catalana de Recerca i Estudis Avançats (ICREA)-IDIBAPS, ; Carrer Casanova 143, 08036 Barcelona, Spain

[6 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Neurology, , University of Pennsylvania, ; 3400 Spruce St, Philadelphia, PA 19104 USA

Author information

Heike Stein http://orcid.org/0000-0002-0871-6076

Joao Barbosa http://orcid.org/0000-0002-1907-3010

Mireia Rosa-Justicia http://orcid.org/0000-0003-4494-0785

Eugenia Martinez-Hernandez http://orcid.org/0000-0002-8317-7068

Josefina Castro-Fornieles http://orcid.org/0000-0003-0632-2687

Josep Dalmau http://orcid.org/0000-0001-5856-2813

Albert Compte http://orcid.org/0000-0001-6594-6946

Article

Publisher ID: 18033

DOI: 10.1038/s41467-020-18033-3

PMC ID: 7447775

PubMed ID: 32843635

SO-VID: 9e4327b7-0c12-4eca-ab0a-ab127c7ff99a

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 December 2019

Date accepted : 31 July 2020

Funding

Funded by: FundRef https://doi.org/10.13039/501100004587, Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III);

Award ID: PIE 16/00014

Award Recipient : Heike Stein Mireia Rosa-Justicia Laia Prades Alba Morató Josefina Castro-Fornieles Josep Dalmau Albert Compte

Funded by: FundRef https://doi.org/10.13039/100010665, EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions);

Award ID: 713673

Award Recipient : Heike Stein

Funded by: FundRef https://doi.org/10.13039/501100002943, Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia);

Award ID: 2014SGR1265

Award ID: 2017SGR01565

Award ID: 2014SGR1265

Award ID: 2017SGR01565

Award ID: 2014SGR1265

Award ID: 2017SGR01565

Award Recipient : Heike Stein Joao Barbosa Alba Morató Albert Compte

Funded by: Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia)

Funded by: FundRef https://doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness);

Award ID: BFU 2015-65318-R

Award ID: RTI2018-094190-B-I00

Award ID: BFU 2015-65318-R

Award ID: RTI2018-094190-B-I00

Award ID: BFU 2015-65318-R

Award ID: RTI2018-094190-B-I00

Award Recipient : Heike Stein Joao Barbosa Alba Morató Albert Compte

Funded by: "La Caixa" Foundation, Ref: LCF/BQ/IN17/11620008

Funded by: Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia)

Funded by: FundRef https://doi.org/10.13039/501100005032, Fundação Bial (Bial Foundation);

Award ID: 356/18

Award Recipient : Joao Barbosa

Funded by: FundRef https://doi.org/10.13039/100008050, Fundación Cellex (Cellex Foundation);

Funded by: "La Caixa" Foundation, Ref: LCF/PR/HR17/52150001

Funded by: Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia)

Funded by: "La Caixa" Foundation, Ref: LCF/PR/HR17/52150001

Funded by: FundRef https://doi.org/10.13039/501100003136, Edmond J. Safra Philanthropic Foundation (Fondation Philanthropique Edmond J. Safra);

Funded by: "La Caixa" Foundation, Ref: LCF/PR/HR17/52150001

Funded by: Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia)

Funded by: "La Caixa" Foundation, Ref: LCF/PR/HR17/52150001

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ScienceOpen disciplines: Uncategorized

Keywords: network models,channelopathies,schizophrenia,working memory,short-term potentiation

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ScienceOpen disciplines: Uncategorized

Keywords: network models, channelopathies, schizophrenia, working memory, short-term potentiation

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

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Most cited references 59

Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex.

Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis.

Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model.

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