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Background:The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP) produced in astrocytes and antagonizes N-methyl-D-aspartate and a7* nicotinic receptors. Methods: The formation of KYNA is determined by the availability of substrate, and hence, we analyzed KYNA and its precursors, kynurenine (KYN) and TRP, in the cerebrospinal fluid (CSF) of patients with schizophrenia. CSF from male patients with schizophrenia on olanzapine treatment (n 5 16) was compared with healthy male volunteers (n 5 29). Results: KYN and KYNA concentrations were higher in patients with schizophrenia (60.7 ± 4.37nM and 2.03 ± 0.23nM, respectively) compared with healthy volunteers (28.6 ± 1.44nM and 1.36 ± 0.08nM, respectively), whereas TRP did not differ between the groups. In all subjects, KYN positively correlated to KYNA. Conclusion: Our results demonstrate increased levels of CSF KYN and KYNA in patients with schizophrenia and further support the hypothesis that KYNA is involved in the pathophysiology of schizophrenia.

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Background:In recent years, a role for the immune system in the pathogenesis of psychiatric diseases has gained increased attention.Although bipolar disorder appears to be associated with altered serum cytokine levels, a putative immunological contribution to its pathophysiology remains to be established. Hitherto, no direct analyses of cerebrospinal fluid (CSF) cytokines in patients with bipolar disorder have been performed. Methods: We analyzed CSF cytokine concentrations in euthymic patients with diagnosed bipolar dis order type I (n = 15) or type II (n = 15) and healthy volunteers (n = 30) using an immunoassay-based protein array multiplex system. Results: The mean interleukin (IL)-1β level (4.2 pg/mL, standard error of the mean [SEM] 0.5) was higher and the IL-6 level (1.5 pg/mL, SEM 0.2) was lower in euthymic bipolar patients than in healthy volunteers (0.8 pg/mL, SEM 0.04, and 2.6 pg/mL, SEM 0.2, respect ively). Patients with 1 or more manic/hypomanic episodes during the last year showed significantly higher levels of IL-1β (6.2 pg/mL, SEM 0.8; n = 9) than patients without a recent manic/hypomanic episode (3.1 pg/mL, SEM 1.0; n = 10). Limitations: All patients were in an euthymic state at the time of sampling. Owing to the large variety of drugs prescribed to patients in the present study, influence of medication on the cytokine profile cannot be ruled out. Conclusion: Our findings show an altered brain cytokine profile associated with the manifestation of recent manic/hypomanic episodes in patients with bipolar disorder. Although the causality remains to be established, these findings may suggest a pathophysiological role for IL-1β in bipolar disorder. In recent years, a role of the immune system in the pathogenesis of psychiatric diseases has gained increased attention. In this regard, many investigators have focused on cytokines, proteins that directly initiate and control immunological responses. We recently demonstrated a selective activation of brain interleukin (IL)-1β in schizophrenia, 2 a disease that appears similar to bipolar disorder with regard to symptomatology, treatment and risk genes. 3,4 Interestingly, a polymorphism in the promoter region of the IL1B gene has been suggested to comprise a shared genetic susceptibility for bipolar disorder and schizophrenia. 5 Indeed, bipolar disorder appears to be linked to inflammation, as indicated by genetic polymorphisms, gene expression and cytokine activation, 6 although direct evidence for a pathophysiological involvement of the immune system of the brain is still sparse. This may be 115 related to the fact that evaluation of cytokine levels in patients with bipolar disorder has been restricted to serum analyses. The bidirectional communication between the immune system of the brain and that of peripheral organs is complex, 7 and serum cytokines do not predict brain cytokine activation in healthy volunteers. 8 Hence, the immune system of the brain, including local cytokine release from microglia and astrocytes, may be independent of the immune sys...

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-d-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

The endocannabinoid system regulates some aspects of the brain's inflammatory response, including the release of pro-inflammatory cytokines and modulation of microglial activation. [1][2][3][4] The endocannabinoid system is composed of two G-proteincoupled receptors designated as CB1 and CB2 expressed throughout the body and notably by neural stem cells. 5 We have previously shown that stimulation of the CB1/2 receptors using a low dose of WIN-55,212-2 significantly reversed the LPS-induced microglia activation in young rats.2 This anti-inflammatory effect was also found in aged rats, attenuating the age-induced performance impairment observed in the water pool task.3 As normal aging is associated with increased levels of microglial activation and a decrease in neurogenesis, both probably contributing to the hippocampus-related memory deficit, we investigated the effects of an agonist of CB1/2 receptors on neurogenesis in the brain of normal aged rats.A total of 12 old (23-month-old) and 6 young (3-month-old) male F-344 rats were chronically infused for 28 days subcutaneously using an osmotic minipump with WIN-55,212-2 (2 mg kg À1 per day n = 6) or the vehicle (n = 12) into the dorsal abdominal area. Two injections of 50 mg kg À1 i.p. of 5-bromo-2-deoxyuridine were made on day 1 and day 2 post surgery to track new cells' production. The rats were assigned to one of the following three groups: youngvehicle (n = 6), old þ vehicle (n = 6) and old þ WIN-55,212-2 2 mg kg À1 per day (n = 6). Doublecortin immunoreactivity was found only in the subgranular zone of the dentate gyrus (DG) of the hippocampus ( Figure 1A). A significant difference (Figure 1Aa-d) in doublecortin immunoreactivity was found between young (3-month-old, 73.125 ± 22.8 cells per DG) and old rats (23-month-old, 3±1.8 P < 0.05). The 4 weeks of WIN 55,212-2 infusion resulted in a significant increase in doublecortin immunoreactivity cells ( þ 116%, F 1, 30 = 6.774, P = 0.0142, ANOVA with Fisher's PLSD post-hoc test) as compared with that in old vehicle-treated controls ( Figure 1B). 5-bromo-2-deoxyuridine immunoreactivity was found sparsely in the cortex and hippocampus of the old vehicle-treated controls. The number of 5-bromo-2-deoxyuridine immunoreactivity cells was counted in the DG; the 4 weeks of WIN-55,212-2 infusion produced a significant increase in 5-bromo-2-deoxyuridine immunoreactivity cells ( þ 63%, F 1, 221 = 12.795, P = 0.0004 ANOVA with Fisher's PLSD post-hoc test) as compared with that in old vehicletreated controls ( Figure 1C). The proportion of newly produced neurons over glial cells was determined and showed no significant difference between control or treated aged rats ( Figure 1D, P = 0.42), confirming the increase in number of neurons engrafted in the DG after the 4-week treatment.Our results confirm that neurogenesis is still present during normal aging in rats, although at a drastically reduced level as compared with that in young rats, for review see Verret et al. 6 We now report that neurogenesis in aged rats can be sign...