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Amygdala levels of the GluA1 subunit of glutamate receptors and its phosphorylation state at serine 845 in the anterior hippocampus are biomarkers of ictal fear but not anxiety

Molecular Psychiatry volume 25, pages 655–665 (2020)Cite this article

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Abstract

Fear is a conscious state caused by exposure to real or imagined threats that trigger stress responses that affect the body and brain, particularly limbic structures. A sub-group of patients with mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) have seizures with fear, which is called ictal fear (IF), due to epileptic activity within the brain defensive survival circuit structures. Synaptic transmission efficacy can be bi-directionally modified through potentiation (long-term potentiation (LTP)) or depression (long-term depression (LTD)) as well as the phosphorylation state of Ser831 and Ser845 sites at the GluA1 subunit of the glutamate AMPA receptors, which has been characterized as a critical event for this synaptic plasticity. In this study, GluA1 levels and the phosphorylation at Ser845 and Ser831 in the amygdala (AMY), anterior hippocampus (aHIP) and middle gyrus of temporal neocortex (CX) were determined with western blots and compared between MTLE-HS patients who were showing (n = 06) or not showing (n = 25) IF. Patients with IF had an 11% decrease of AMY levels of the GluA1 subunit (p = 0.05) and a 21.5% decrease of aHIP levels of P-GluA1-Ser845 (p = 0.009) compared to patients not showing IF. The observed associations were not related to imbalances in the distribution of other concomitant types of aura, demographic, clinical or neurosurgical variables. The lower levels of P-GluA1-Ser845 in the aHIP of patients with IF were not related to changes in the levels of the serine/threonine-protein phosphatase PP1-alpha catalytic subunit or protein kinase A activation. Taken together, the GluA1 subunit levels in AMY and P-GluA1-Ser845 levels in the aHIP show an overall accuracy of 89.3% (specificity 95.5% and sensitivity 66.7%) to predict the presence of IF. AMY levels of the GluA1 subunit and aHIP levels of P-GluA1-Ser845 were not associated with the psychiatric diagnosis and symptoms of patients. Taken together with previous findings in MTLE-HS patients with IF who were evaluated by stereotactic implanted depth electrodes, we speculate our findings are consistent with the hypothesis that AMY is not a centre of fear but together with other sub-cortical and cortical structures integrates the defensive circuit that detect and respond to threats. This is the first report to address neuroplasticity features in human limbic structures connected to the defensive survival circuits, which has implications for the comprehension of highly prevalent psychiatric disorders and symptoms.

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Acknowledgements

This work was supported by PRONEX Program (Programa de Núcleos de Excelência–NENASC Project) of FAPESC-CNPq-MS, Santa Catarina Brazil (process 56802/2010). MRC 271-05-0712 (ZAB) and FAPESC-CONFAP–THE UK ACADEMIES–2016 (ZAB and RW). Professor Dr. Peter Wolf is Special Visitor Researcher (Process 88881.030478/2013-01) supported by MEC/MCTI/CAPES/CNPq/FAPs. We thank David Lodge (School of Physiology, Pharmacology and Neuroscience, University of Bristol) for the English revision. RBL, AL, RDP, KL and RW are researchers from the Brazilian National Council for Scientific and Technological Development (CNPq). RBL and RW dedicate this work to Professor Dr. Ivan A. Izquierdo for his teachings about neurobiology of aversive memory and “in memoriam” to Professor Dr. Richard Rodnight for his teachings in phospho-proteins and signal transduction.

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    Authors and Affiliations

    1. Center for Applied Neuroscience, University Hospital, UFSC, Florianópolis, SC, Brazil

      Rodrigo Bainy Leal, Mark William Lopes, Douglas Affonso Formolo, Cristiane Ribeiro de Carvalho, Alexandre Ademar Hoeller, Alexandra Latini, Daniel Santos Sousa, Rui Daniel Prediger, Marcelo Neves Linhares, Kátia Lin & Roger Walz

    2. Department of Biochemistry, UFSC, Florianópolis, SC, Brazil

      Rodrigo Bainy Leal, Mark William Lopes & Alexandra Latini

    3. Graduate Program in Neuroscience, UFSC, Florianópolis, SC, Brazil

      Rodrigo Bainy Leal, Douglas Affonso Formolo, Cristiane Ribeiro de Carvalho, Rui Daniel Prediger & Roger Walz

    4. Graduate Program in Medical Sciences, UFSC, Florianópolis, SC, Brazil

      Alexandre Ademar Hoeller, Daniel Santos Sousa, Peter Wolf, Kátia Lin & Roger Walz

    5. Neurosurgery Unit, Governador Celso Ramos Hospital, Florianópolis, SC, Brazil

      Daniel Santos Sousa & Marcelo Neves Linhares

    6. Department of Internal Medicine, Neurology Service, University Hospital, UFSC, Florianópolis, SC, Brazil

      Peter Wolf, Kátia Lin & Roger Walz

    7. Department of Pharmacology, UFSC, Florianópolis, SC, Brazil

      Rui Daniel Prediger

    8. Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK

      Zuner Assis Bortolotto

    9. Center for Epilepsy Surgery of Santa Catarina (CEPESC), University Hospital, UFSC, Florianópolis, SC, Brazil

      Marcelo Neves Linhares, Kátia Lin & Roger Walz

    10. Neurosurgery Division, Department of Surgery, University Hospital, UFSC, Florianópolis, SC, Brazil

      Marcelo Neves Linhares

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    Leal, R.B., Lopes, M.W., Formolo, D.A. et al. Amygdala levels of the GluA1 subunit of glutamate receptors and its phosphorylation state at serine 845 in the anterior hippocampus are biomarkers of ictal fear but not anxiety. Mol Psychiatry 25, 655–665 (2020). https://doi.org/10.1038/s41380-018-0084-7

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