Abstract: The kynurenic acid (KYNA) hypothesis of schizophrenia is based on findings that patients with schizophrenia display elevated levels of KYNA in the cerebrospinal fluid (CSF) and postmortem brain. In patients with bipolar disorder, elevated brain levels of KYNA associate with psychotic features and cognitive dysfunctions. Studies in rodents demonstrate that experimentally induced elevation of brain KYNA causes alterations in glutamatergic and dopaminergic neurotransmission to induce psychosis and cognitive dysfunction.
We have now investigated the status of central KYNA in two other clinically relevant conditions that are linked to an activated immune system: 1) Patients infected with Covid-19 and 2) Mice with a deletion of GRK3, a member of the G protein-coupled receptor kinase family (expression of GRK3 is significantly reduced in the prefrontal cortex of persons with SZ). Blockade of kynurenine aminotransferases (KAT) II significantly reduces KYNA in control rats, recent data from our lab reveal though that immune activation increases the production of KYNA by inducing another KAT enzyme. In this talk, data on this target will be presented.
Methods: CSF KYNA was measured with LC/MS in 59 patients with SARS-CoV-2 infection and 33 age- and sex-matched healthy controls (HC). Of the patients, 48 were treated at an intensive care unit (ICU) and 11 were enrolled after discharge from the hospital and following seeking psychiatric care. Kruskal-Wallis one-way ANOVA followed by Mann-Whitney U-test was used for statistical analysis. Adult male C57Bl/6J (Grk3+/+) and Grk3-/- mice were used. Cytokines were analyzed using a Human Ultra-Sensitive 10-Plex Kit (MesoScale Discovery). KYNA and dopamine was estimated by microdialysis, followed by HPLC detection. Psychosis-like phenotypes were examined using novelty-induced hypermotility, prepulse inhibition (PPI), and D-amphetamine-induced hypermotility. For details see Sellgren et al., 2021. In vivo electrophysiology of VTA dopamine neurons was performed to characterize dopaminergic firing pattern. Gaussian distribution was tested using D'Agostino & Pearson normality test and parametric tests were used where appropriate. All tests were two-tailed with alpha set to 0.05. Sample sizes were chosen to reflect at least 80% power, assuming effect sizes such as in similar and previous experiments.
Results: CSF KYNA was 10 times higher in patients with Covid-19 than in HC (13.2±2.4 nM; n=48 vs. 1.26±0.15 nM; n=33) (p<0.0001), Three weeks after discharge from the hospital, levels of CSF KYNA were still elevated (1.96 ±0.31 nM, n=11, p=0.0494). Compared to Grk3+/+, Grk3-/- mice showed a number of aberrations, including elevated brain levels of IL-1beta, increased turnover of KYNA, and a hyper-reactive response to D-amphetamine regarding locomotor activity and striatal dopamine release. Also, these mice showed an elevated spontaneous firing of midbrain dopamine neurons, as well as a disruption in PPI, and attentional deficits.
Conclusion: Our finding that the CSF levels of KYNA are elevated during and in the aftermath of a Covid-19 infection suggests that increased brain KYNA may be relevant for long-Covid symptomatology, such as fatigue, brain fog and cognitive decline. Together with the results of our study in Grk3-/- mice, which show neurochemical and behavioral abnormalities reminiscent of SZ, our new data bode well for future novel, KYNA-focused therapeutics in SZ and other immune-related diseases affecting the brain.
Sophie Erhardt is Professor in Experimental Psychiatry at Karolinska Institutet in Stockholm, Sweden. Her research is focused on understanding the pathophysiology of severe psychiatric disorders to identify novel pharmaceutical targets. In particular, she studies how the immune system interacts with the kynurenine pathway and associates it with behavior.
During her Ph.D., Sophie was the first to show that kynurenic acid, is elevated in the CSF of patients with schizophrenia. She carried out postdoctoral work in Professor Mark Geyer’s lab at the USCD, USA, and showed that increased levels of kynurenic acid were associated with disrupted PPI, a core feature of schizophrenia.
After completing her postdoctoral training, Sophie set up her laboratory at Karolinska Institutet, continuing to investigate the underlying immunological mechanisms of schizophrenia, bipolar disorder, and suicidality and the fact that early-life changes in kynurenic acid concentrations could contribute to the development of schizophrenia.
Dr. Erhardt became a full professor at the Karolinska Institutet, Stockholm, Sweden in 2016 and has supervised 14 Ph.D. students up to the thesis defense. She is the PI of a large drug discovery project that is currently in the lead generation phase. Dr. Erhardt was recently awarded the Maltz Prize for Innovative & Promising Schizophrenia Research from the Brain & Behavior Research Foundation
