Glutamate Function in Health and Disease
Glutamate is a neurotransmitter that plays a pivotal role in synaptic transmission and excitatory signaling within the brain. Dysregulation of the glutamate system has been implicated in various mental disorders, including major depression, bipolar disorder, substance use disorder, and schizophrenia. Early detection and intervention targeting the glutamate system could hold promise for improving treatment outcomes and mitigating the progression of these conditions.
Past research of Prof. Gregor Hasler has resulted in the discovery of a glutamate receptor subtype, mGluR5, which serves as a biomarker for nicotine dependence. The research, which used positron emission tomography methods, found the receptor subtype to be 30 percent less abundant in the brains of smokers. After a prolonged period of abstinence, a normalization of the receptor levels was observed. These findings inspired applied research for mGluR5-targeting drugs for the treatment of nicotine addiction. We have also studied drugs that target the glutamate system; namely ketamine, an antagonist at the NMDA glutamate receptor subtype. We examined the effects of ketamine on depression patients who did not respond to standard treatments. Our findings aligned with the broader literature, showing a rapid and sustainable antidepressant effect.
The molecular psychiatry laboratory examines glutamate neurotransmission in several ongoing studies employing sophisticated molecular imaging techniques, including magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) methods. These methods enable precise measurements of glutamate concentrations and receptor activity, providing valuable insights into the pathophysiology of psychiatric disorders. For example, one of our studies examines glutamate function in the early phases of psychotic disorders.
Current Studies
The GLUMULTI study is a study combining positron emission tomography (PET), magnetic resonance imaging (MRI), and clinical assessment methods to examine the importance of the glutamate system in explaining early signs of psychosis.
The GABAGEN study is a multi-method cohort study in which we collected glutamate and glutamate-related measurements using magnetic resonance spectroscopy (MRS) and associate them with various health and disease states using (among other methods) stool sampling; genetic, epigenetic, and transcriptomic next-generation sequencing; cytokine profiling; electrocardiogram; clinical interviews; behavioral experiments; and psychological questionnaires.
Publications
Akkus, F., Ametamey, S. M., Treyer, V., Burger, C., Johayem, A., Umbricht, D., Gomez Mancilla, B., Sovago, J., Buck, A., & Hasler, G. (2013). Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [11C]ABP688 positron emission tomography. Proceedings of the National Academy of Sciences of the United States of America, 110(2), 737–742. https://doi.org/10.1073/pnas.1210984110
Akkus, F., Mihov, Y., Treyer, V., Ametamey, S. M., Johayem, A., Senn, S., Rösner, S., Buck, A., & Hasler, G. (2018). Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder. Translational psychiatry, 8(1), 17. https://doi.org/10.1038/s41398-017-0066-6
Akkus, F., Terbeck, S., Ametamey, S. M., Rufer, M., Treyer, V., Burger, C., Johayem, A., Mancilla, B. G., Sovago, J., Buck, A., & Hasler, G. (2014). Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder. The international journal of neuropsychopharmacology, 17(12), 1915–1922. https://doi.org/10.1017/S1461145714000716
Akkus, F., Terbeck, S., Haggarty, C. J., Treyer, V., Dietrich, J. J., Hornschuh, S., & Hasler, G. (2020). The role of the metabotropic glutamate receptor 5 in nicotine addiction. CNS spectrums, 1–6. Advance online publication. https://doi.org/10.1017/S1092852920001704
Akkus, F., Treyer, V., Ametamey, S. M., Johayem, A., Buck, A., & Hasler, G. (2017). Metabotropic glutamate receptor 5 neuroimaging in schizophrenia. Schizophrenia research, 183, 95–101. https://doi.org/10.1016/j.schres.2016.11.008
Akkus, F., Treyer, V., Johayem, A., Ametamey, S. M., Mancilla, B. G., Sovago, J., Buck, A., & Hasler, G. (2016). Association of Long-Term Nicotine Abstinence With Normal Metabotropic Glutamate Receptor-5 Binding. Biological psychiatry, 79(6), 474–480. https://doi.org/10.1016/j.biopsych.2015.02.027
Deschwanden, A., Karolewicz, B., Feyissa, A. M., Treyer, V., Ametamey, S. M., Johayem, A., Burger, C., Auberson, Y. P., Sovago, J., Stockmeier, C. A., Buck, A., & Hasler, G. (2011). Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. The American journal of psychiatry, 168(7), 727–734. https://doi.org/10.1176/appi.ajp.2011.09111607
Guglielmo, R., & Hasler, G. (2022). The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder. Neuroscience and biobehavioral reviews, 142, 104906. https://doi.org/10.1016/j.neubiorev.2022.104906
Hasler, G., Buchmann, A., Haynes, M., Müller, S. T., Ghisleni, C., Brechbühl, S., & Tuura, R. (2019). Association between prefrontal glutamine levels and neuroticism determined using proton magnetic resonance spectroscopy. Translational psychiatry, 9(1), 170. https://doi.org/10.1038/s41398-019-0500-z
Hasler, G., & Northoff, G. (2011). Discovering imaging endophenotypes for major depression. Molecular psychiatry, 16(6), 604–619. https://doi.org/10.1038/mp.2011.23
Mihov, Y., & Hasler, G. (2016). Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window. The international journal of neuropsychopharmacology, 19(7), pyw002. https://doi.org/10.1093/ijnp/pyw002
Mihov, Y., Treyer, V., Akkus, F., Toman, E., Milos, G., Ametamey, S. M., Johayem, A., & Hasler, G. (2020). Metabotropic glutamate receptor 5 in bulimia nervosa. Scientific reports, 10(1), 6374. https://doi.org/10.1038/s41598-020-63389-7
Müller Herde, A., Mihov, Y., Krämer, S. D., Mu, L., Adamantidis, A., Ametamey, S. M., & Hasler, G. (2019). Chronic Nicotine Exposure Alters Metabotropic Glutamate Receptor 5: Longitudinal PET Study and Behavioural Assessment in Rats. Neurotoxicity research, 36(4), 806–816. https://doi.org/10.1007/s12640-019-00055-5
Terbeck, S., Akkus, F., Chesterman, L. P., & Hasler, G. (2015). The role of metabotropic glutamate receptor 5 in the pathogenesis of mood disorders and addiction: combining preclinical evidence with human Positron Emission Tomography (PET) studies. Frontiers in neuroscience, 9, 86. https://doi.org/10.3389/fnins.2015.00086
