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Antibodies to NMDA receptor, blood–brain barrier disruption and schizophrenia: a theory with unproven links

Molecular Psychiatry volume 19, page 1054 (2014)Cite this article

Subjects

Hammer et al.1 examined 2817 subjects, including 1325 healthy subjects and patients with schizophrenia (1081), Parkinson disease (263) and affective disorders (148) for the presence of several immunoglobulin subtypes of antibodies against the NR1 subunit of the NMDA receptor (NMDAR). In this large-scale screening, they found that 10.5% of all subjects were seropositive. The authors conclude that schizophrenic individuals with a past or present history of blood–brain barrier (BBB) disturbance are more likely to have more pronounced neurological symptoms upon NMDAR antibody seropositivity. However, there is no data supporting this conclusion in any of the sections of the manuscript:

  1. 1)

    The authors’ conclusion was based on retrospective review of clinical information for possible neurotrauma at birth or thereafter in the patients and controls. Even assuming that there was neurotrauma (which in fact is not clearly demonstrated), the authors do not provide any evidence that it altered the integrity of the BBB.

  2. 2)

    In the experiments with cultured neurons the authors claim that decreased NMDAR immunostaining was visible with confocal microscopy after incubation with patients’ antibodies for 20 min, ‘subsequently placing the cells in pre-warmed growth medium for 15 min to allow internalization.’ However, other than a graph, there is no data showing confocal microscopy pictures of the density of cell surface/synaptic NMDAR clusters before and after incubation with patients’ antibodies. The findings are hard to explain given that studies by other investigators on antibody-mediated NMDAR internalization using patient samples with very high titer antibodies (for example, those with anti-NMDAR encephalitis) found no detectable internalization using confocal microscopy until ~4 h after neuronal incubation, reaching a plateau at ~24 h.2,3

  3. 3)

    In contrast to the authors’ suggestion, the mouse experiments do not provide supporting evidence to their interpretation of the patients’ findings (point 1). For this, in the minimum, the authors should demonstrate that the systemic injection of patients’ immunoglobulin G (IgG) reaches the brain of mice, binds to NMDAR and alters receptor levels and function.

The authors’ conclusion was based on retrospective review of clinical information for possible neurotrauma at birth or thereafter in the patients and controls. Even assuming that there was neurotrauma (which in fact is not clearly demonstrated), the authors do not provide any evidence that it altered the integrity of the BBB.

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References

  1. Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M et al. Mol Psychiatry advance online publication, 3 September 2013; doi:10.1038/mp.2013.110 (e-pub ahead of print).

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  4. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S et al. JAMA Psychiatry 2013; 70: 271–278.

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  5. Gresa-Arribas N, Titulaer MJ, Torrents A, Aguilar E, McCracken L, Leypoldt F et al. Lancet Neurol 2013; 13: 167–177.

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Acknowledgements

Dr Titulaer is supported by grants from the Netherlands Organisation for Scientific Research (NWO, Veni-incentive), the Dutch Epilepsy Foundations (project number 14–19), an ErasmusMC fellowship and previously a clinical research fellowship by the Dutch Cancer Society (2009–4451). Dr Dalmau is supported by grants from the National Institutes of Health RO1NS077851, Fundació la Marató TV3 and Fondo de Investigaciones Sanitarias (FIS, PI11/01780).

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Authors and Affiliations

  1. Department of Neurology at Hospital Clinic—Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    M J Titulaer & J Dalmau

  2. Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands,

    M J Titulaer

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    J Dalmau

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  1. M J Titulaer
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Correspondence to J Dalmau.

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Competing interests

Dr Dalmau holds a patent application for the use of NMDA receptor as antibody test, and has received a research grant for Euroimmun. Dr Titulaer received a travel grant for lecturing in India from Sun Pharma, India.

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Titulaer, M., Dalmau, J. Antibodies to NMDA receptor, blood–brain barrier disruption and schizophrenia: a theory with unproven links. Mol Psychiatry 19, 1054 (2014). https://doi.org/10.1038/mp.2014.25

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