Research in our group concerns 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 own 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 and we will, in collaboration with a medical chemistry group in Groningen, The Netherlands, develop novel compounds to inhibit kynurenine aminotransferase (KAT II), which should decrease brain concentration 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.
Please see the Neuropsychoimmunology research group
Investigations of the physiological significance of endogenous brain KYNA
These studies include analyses of firing of midbrain DA neurons as well as of the release of DA in prefronal 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 (for example a blockade of the glycine/serine transporter; Schwieler et al., 2004).
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 analysis of other "atypical" antipsychotic drugs, i.e. olanzapine, quetiapine, and risperidone.
Cerebrospinal fluid (CSF) from schizophrenic patients
These studies include analysis of CSF KYNA from patients with schizophrenia as well as from patients with virus infektion, for example HIV, TBE, herpes etc.
In collaboration with Professor Hashimoto (Chiba University, Japan) we investigate the role of glutamate and D-serine in schizophrenia. In a recent report we find that the glutamine/glutamate ratio in CSF is elevated in drug schizophrenic patients.
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?
Numerous studies points to an involvement of viral or immunological process in the pathophysiology of schizophrenia. A problem with this idea however, is that schizophrenic symptoms in all probability are mediated via midbrain dopaminergic system and no convincing mechanism has been provided to explain how inflammatory processes produce hyperdopaminergia.
In our investigations, we will study the importance of endogenous KYNA as a critical link in this regard.
Synthesis of inhibitors of kynurenine aminotransferas in order to develop novel treatment strategies for schizophrenia
The enzyme responsible for the immediate formation of brain KYNA is kynurenine aminotransferase (KAT). The enzyme exists in at least three different isoforms, of which KAT II appears functionally most important for central KYNA synthesis. Inhibition of KAT II should definitively result in a lowering in brain KYNA concentration. However, the lack of specific inhibitors of KAT II has hampered the research on KYNA for many years.
Together with University of Groningen we develop novel drugs to decrease the synthesis of KYNA (KAT II inhibitors).
Given a role of KYNA in the pathophysiology of schizophrenia, the availability of such agents would certainly offer a novel approach in the treatment of the disease. The specificity of these drugs will be analysed utilizing electrophysiological studies, biochemical assessment of KYNA and in behavioral models (prepulse inhibition).
- Single cell recordings techniques including microiontophoresis
- Microdialysis techniques with HPLC detection of KYNA and DA
- Prepulse inhibition techniques (PPI)
Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder.
J Psychiatry Neurosci 2010 May;35(3):195-9
Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders.
CNS Drugs 2009 ;23(2):91-101
Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia.
Int. J. Neuropsychopharmacol. 2009 May;12(4):501-12
Activation of brain interleukin-1beta in schizophrenia.
Mol. Psychiatry 2009 Dec;14(12):1069-71
Induction of the kynurenine pathway by neurotropic influenza A virus infection.
J. Neurosci. Res. 2008 Dec;86(16):3674-83
The kynurenic acid hypothesis of schizophrenia.
Physiol. Behav. 2007 Sep;92(1-2):203-9
Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis.
Neuropharmacology 2007 Dec;53(8):918-24