Research in our group aims to gain a better understanding of the pathophysiology of the disease schizophrenia, so as to contribute to the elaboration of new and more effective drugs.
Our research is based on our discovery that the brain's immune system is activated in psychiatric disorders. We aim to understand the neuropsychoimmunological mechanisms involved in the pathophysiology of schizophrenia, bipolar disorder and depression.
|Ada Trepci||Doktorand, Forskarstuderande|
|Maximilian Tufvesson Alm||Doktorand|
|Group members outside of KI|
Disease Area Expert, TI at AstraZeneca, Mölndal
|Robert Schwarcz||Foreign adjunct professor|
Please also see the Electrophysiological neuropharmacology research group.
The focus of our research is the glial cells in the brain. These cells have previously been regarded as mere support cells in the brain, but recent research clearly shows that glial cells exert a number of important functions, including those involved in the brain's own immune system.
Our hypothesis is that gliotransmitters, that is substances that are released from glial cells - such as kynurenic acid and cytokines (immune system neurotransmitters) - are involved in the pathophysiology of mental illness, and that control functions that normally control the synthesis and release of these gliotransmitters are set out of play in mental illness.
The cytokines that we find activated in mental illness is mainly interleukin (IL)-1 beta in schizophrenia and bipolar disorder, and IL-6 in depression. In animal models it is known that cytokines have the ability to increase the synthesis of kynurenic acid, a naturally occurring glutamate and nicotine receptor antagonist. We have previously shown that patients with psychiatric illness, such as schizophrenia and bipolar disorder, have elevated concentrations of kynurenic acid in the cerebrospinal fluid.
Interactions between cytokines and kynurenic acid
In our future studies, we will perform more in-depth analyses of interactions between cytokines and kynurenic acid. We want to study if it is the kynurenic acid activating cytokines, or vice versa. All of these substances are interestingly enough synthesized and released from the same type of cells in the brain: astrocytes and microglia. An important factor for the activity of astrocytes is intracellular signaling pathways such as mTOR, MAPK or NF-kappa B. We know that these are important for the activation of the innate immune system and general astrocyte function (size, differentiation, proliferation and migration). A disturbance in the intracellular signaling could be responsible for the activation of cytokines and the increase of kynurenic acid observed in the cerebrospinal fluid of patients with mental illness. It is therefore important to examine not only how intracellular signaling activates cytokines and directs the synthesis of kynurenic acid, but also how the activity of the cytokines is regulated. The hypothesis is that the key control functions that normally control the activity of signaling pathways are set out of play in patients with psychiatric illnesses. To explore these signaling pathways in disease-specific conditions, we will grow monocytes from individuals with different types of mental illness. Access to these gives us a unique opportunity to study specific disease mechanisms, and thus gain knowledge of the pathophysiology of psychiatric disorders. On the basis of these and other studies, we hope to propose new specific targets for future drug treatment of these diseases.
In another project, we study whether the increased levels of cytokines and kynurenic acid can induce morphological abnormalities, similar to those previously reported in patients with psychiatric disorders. In a third project, we study whether increased levels of cytokines and kynurenic acid in the brains of rodents can cause behavioral abnormalities that mimic those that patients with psychiatric illness have.
Our research team works in close co-operation with several national and international researchers and is part of the Karolinska Schizophrenia Project (KASP). Among our partners are experts with extensive experience in clinical psychiatric research, behavioral pharmacology, immunology, and basic molecular biology research. This constellation of researchers enables a deeper understanding of how psychiatric disorders arise.
At the Department of Physiology and Pharmacology, Karolinska Institutet we have an ongoing collaboration with the Electrophysiological neuropharmacology research group.
Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters.
Psychoneuroendocrinology 2013 Jun;38(6):853-62
Connecting inflammation with glutamate agonism in suicidality.
Neuropsychopharmacology 2013 Apr;38(5):743-52
CSF kynurenic acid and suicide risk in schizophrenia spectrum psychosis.
Psychiatry Res 2013 Jan;205(1-2):165-7
Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder.
Bipolar Disord 2012 Nov;14(7):719-26
Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls.
J Psychiatry Neurosci 2012 Jan;37(1):53-7
Subchronic elevation of brain kynurenic acid augments amphetamine-induced locomotor response in mice.
J Neural Transm (Vienna) 2012 Feb;119(2):155-63
Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia.
Schizophr Bull 2012 May;38(3):426-32
CSF biomarkers in suicide attempters--a principal component analysis.
Acta Psychiatr Scand 2011 Jul;124(1):52-61