Research in our group focuses on the role of endogenous kynurenic acid in the pathogenesis of schizophrenia.
For decades, theories on the pathophysiology of schizophrenia have focused on dopamine (DA). However, in the past few years, it has become clear that DA is just part of the story and that the main abnormalities lie elsewhere. In particular, suspicion has fallen on deficiencies in glutamate. Our hypothesis is based on our finding that schizophrenic patients have elevated CSF-levels of kynurenic acid (KYNA).
KYNA is an NMDA-receptor antagonist present in astrocytes of the brain. Utilizing a broad spectrum of techniques, including, for example, electrophysiology, microdialysis, prepulse inhibition, and molecular biology techniques, the overall aim of this project is to analyze the physiological and pharmacological significance of KYNA for brain glutamatergic neurotransmission.
Our experiments also attempt to strengthen the idea that KYNA participates in the pathogenesis of schizophrenia. In collaboration with SciLifeLab, Drug Discovery, and Development Platform in Uppsala, we are currently developing novel compounds to reduce brain levels of KYNA. These compounds will not only serve as important scientific tools - they may also offer a unique strategy in the pharmacological treatment of schizophrenia.
Investigations of the physiological significance of endogenous brain KYNA
These studies include analyses of the firing of midbrain DA neurons and the release of DA in the prefrontal cortex and nucleus accumbens following pharmacological manipulation with endogenous concentrations of brain KYNA.
Interaction of endogenous KYNA with antipsychotic drugs
Data from our laboratory describe interactions between brain KYNA and the antipsychotic drugs clozapine on the neuronal activity of midbrain DA neurons, as well as of noradrenergic locus coeruleus neurons.
Briefly, our data point out an action of clozapine at the glycine modulatory site of the NMDA-receptor. Such a glycine agonistic action of clozapine could well account for its therapeutic properties since clozapine stimulates the same site as is blocked by KYNA. Follow-up studies include similar analyses of other "atypical" antipsychotic drugs, i.e. olanzapine, quetiapine, and risperidone.
Cerebrospinal fluid (CSF) from patients with schizophrenia
These studies include analysis of CSF KYNA from patients with schizophrenia (recruited from the Karolinska Schizophrenia Project, as well as from patients with virus infection, for example, HIV, TBE, herpes, etc.
Do polymorphisms of genes encoding for enzymes of the kynurenine metabolism account for the elevated levels of KYNA observed in patients with schizophrenia? This issue is presently being investigated together with Professor Martin Schalling at the Karolinska Institutet.
Studies regarding the role of KYNA in neurodevelopment and neuroplasticity
Epidemiological, clinical, neuropsychological, and neurophysiological studies have provided substantial evidence that abnormalities in brain development and ongoing neuroplasticity play important roles in the pathogenesis of the disorder. Clearly, glutamate plays a major role in processes related to plasticity and several studies have shown a decreased proliferation following treatment with NMDA-receptor antagonists.
Our project in this regard will be focused on changes in e.g. proliferation and connectivity of cortical neurons following elevation of brain KYNA in newborn rats.
In collaboration with Professor Mark Geyer (University of California, San Diego, USA) we are currently investigating the correlation between endogenous KYNA and deficits in prepulse (Prepulse inhibition techniques, PPI) in rats reared in social isolation. Isolation rearing of rats is a developmentally specific, non-pharmacological manipulation that leads to deficits in PPI in adult rats that mimic those observed in patients suffering from schizophrenia.
Thus, isolation rearing has been used as a neurodevelopmental model to examine the pathophysiology of schizophrenia. Our pilot data indicate that those rats have elevated KYNA levels in the hippocampus. It is consistently demonstrated that the PPI-disruptive effects of exogenously administered NMDA antagonists in rodents is one of the most reliable effects in the PPI literature.
Thus, elevated levels of KYNA may be a mechanism through which isolation rearing exerts its disruptive effects on sensorimotor gating in rats.
Inflammatory processes: is KYNA the mediator of psychotic symptoms following activation of the immune system?
Understanding the pathophysiology of schizophrenia is a prerequisite for the development of improved treatments and rational drug design. Although direct evidence for a central role of the immune system in the pathology was sparse for a long time and restricted to epidemiological studies, the view is now strengthened by direct biochemical and genetic evidence.
Using a sensitive assay, we have shown that the pro-inflammatory cytokine interleukin (IL)-1beta is markedly elevated in the cerebrospinal fluid (CSF) of first-episode patients with schizophrenia. This finding was the first directly showing an immune activation in the brain of patients with schizophrenia, and it is nowadays generally accepted world-widely that psychiatric diseases, in general, involve a critical component of brain immune activation.
We have shown repeatedly that cytokines critically regulate the kynurenine pathway and that KYNA serves as a linked to transfer information from the immune system to neuronal circuits.
- Single cell recordings techniques including microiontophoresis
- Microdialysis techniques with HPLC detection of KYNA and DA
Neurogranin as a potential synaptic marker in the cerebrospinal fluid of patients with a first episode psychosis.
Santillo AF, Lundgren S, Xu C, Orhan F, Fatouros-Bergman H, Blennow K, et al
Schizophr Res 2019 06;208():490-492
Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia.
Tufvesson-Alm M, Schwieler L, Schwarcz R, Goiny M, Erhardt S, Engberg G
Neuropharmacology 2018 08;138():130-139
CSF GABA is reduced in first-episode psychosis and associates to symptom severity.
Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, , et al
Mol Psychiatry 2018 05;23(5):1244-1250
Cerebrospinal fluid kynurenine and kynurenic acid concentrations are associated with coma duration and long-term neurocognitive impairment in Ugandan children with cerebral malaria.
Holmberg D, Franzén-Röhl E, Idro R, Opoka RO, Bangirana P, Sellgren CM, et al
Malar J 2017 07;16(1):303
Decreased levels of kynurenic acid in prefrontal cortex in a genetic animal model of depression.
Liu XC, Erhardt S, Goiny M, Engberg G, Mathé AA
Acta Neuropsychiatr 2017 Feb;29(1):54-58
The kynurenine pathway in schizophrenia and bipolar disorder.
Erhardt S, Schwieler L, Imbeault S, Engberg G
Neuropharmacology 2017 Jan;112(Pt B):297-306
A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.
Sellgren CM, Kegel ME, Bergen SE, Ekman CJ, Olsson S, Larsson M, et al
Mol Psychiatry 2016 10;21(10):1342-50
Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons.
Linderholm KR, Alm MT, Larsson MK, Olsson SK, Goiny M, Hajos M, et al
Neuropharmacology 2016 Mar;102():42-7
Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.
Olsson SK, Samuelsson M, Saetre P, Lindström L, Jönsson EG, Nordin C, et al
J Psychiatry Neurosci 2010 May;35(3):195-9
Activation of brain interleukin-1beta in schizophrenia.
Söderlund J, Schröder J, Nordin C, Samuelsson M, Walther-Jallow L, Karlsson H, et al
Mol. Psychiatry 2009 Dec;14(12):1069-71
Induction of the kynurenine pathway by neurotropic influenza A virus infection.
Holtze M, Asp L, Schwieler L, Engberg G, Karlsson H
J. Neurosci. Res. 2008 Dec;86(16):3674-83
Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area.
Schwieler L, Linderholm KR, Nilsson-Todd LK, Erhardt S, Engberg G
Life Sci. 2008 Aug;83(5-6):170-5
The kynurenic acid hypothesis of schizophrenia.
Erhardt S, Schwieler L, Nilsson L, Linderholm K, Engberg G
Physiol. Behav. 2007 Sep;92(1-2):203-9