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A Glutamate Transporter EAAT1 Gene Variant Influences Amygdala Functional Connectivity in Bipolar Disorder

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Abstract

Bipolar disorder (BD) is a severe illness characterized by recurrent depressive and manic episodes and by emotional dysregulation. Altered cortico-limbic connectivity could account for typical symptoms of the disorder such as mood instability, emotional dysregulation, and cognitive deficits. Functional connectivity positively associated with glutamatergic neurotransmission. The inactivation of glutamate is handled by a series of glutamate transporters, among them, the excitatory amino acid transporter 1 (EAAT1) which is modulated by a SNP rs2731880 (C/T) where the C allele leads to increased EAAT1 expression and glutamate uptake. We hypothesized that rs2731880 would affect cortico-limbic functional connectivity during an implicit affective processing task. Sixty-eight BD patients underwent fMRI scanning during implicit processing of fearful and angry faces. We explored the effect of rs2731880 on the strength of functional connectivity from the amygdalae to the whole brain. A significant activation in response to emotional processing was observed in two main clusters encompassing the right and left amygdala. Amygdalae to whole-brain functional connectivity analyses revealed a significant interaction between rs2731880 and the task (emotional stimuli vs geometric shapes) for the functional connections between the right amygdala and right subgenual anterior cingulate cortex. Post-hoc analyses revealed that T/T patients showed a significant negative connectivity between the amygdala and anterior cingulate cortex compared to C carriers. T/T subjects also performed significantly better in the face-matching task than rs2731880*C carriers. Our findings reveal an EAAT1 genotype-associated difference in cortico-limbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of emotional dysfunction in BD.

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Funding

The C.E.R.M.A.C. received unrestricted research grants from the Italian Ministry of Health (RF-2011-02350980), from the European Union (7th framework program, grant 222963), from Trenta ore per la Vita Association, and from Janssen-Cilag. B.V. was supported by Fondazione Umberto Veronesi.

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  1. Psychiatry and Clinical Psychobiology, Division of Neuroscience, Scientific Institute and University Vita-Salute San Raffaele, Milan, Italy

    Sara Poletti, Martina Riberto, Benedetta Vai, Davide Ghiglino, Cristina Lorenzi, Alice Vitali, Silvia Brioschi, Clara Locatelli, Cristina Colombo & Francesco Benedetti

  2. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy

    Alessandro Serretti

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  1. Sara Poletti
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Correspondence to Sara Poletti.

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All the research activities were approved by the local ethical committee. The work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).

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Poletti, S., Riberto, M., Vai, B. et al. A Glutamate Transporter EAAT1 Gene Variant Influences Amygdala Functional Connectivity in Bipolar Disorder. J Mol Neurosci 65, 536–545 (2018). https://doi.org/10.1007/s12031-018-1138-7

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