Paliperidone Reversion of Maternal Immune Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways

Emerging evidence indicates that early-life exposure to environmental factors may increase the risk for schizophrenia via inflammatory mechanisms. Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine pathways in the maternal immune activation (MIA) animal model of schizophrenia. The potential reversion exerted by long-term antipsychotic treatment was also evaluated. MIA was induced by prenatal administration of polyinosinic:polycytidylic acid (poly (I:C)) in mice. Expression of different proteins and the content of different metabolites involved in the function of serotonergic and kynurenine pathways was assessed by RT-PCR, immunoblot and ELISA analyses in frontal cortex of the offspring after puberty. MIA decreased tissue 5-HT content and promoted changes in the expression of serotonin transporter, 5-HT2A and 5-HT2C receptors. Expression of indoleamine 2,3-dioxygenase 2 (IDO2) and kynurenine 3-monooxygenase (KMO) was increased by poly (I:C) whereas kynurenine aminotransferase II and its metabolite kynurenic acid were not altered. Long-term paliperidone was able to counteract MIA-induced changes in 5-HT and KMO, and to increase tryptophan availability and tryptophan hydroxylase-2 expression in poly (I:C) mice but not in controls. MIA-induced increase of the cytotoxic risk ratio of kynurenine metabolites (quinolinic/kynurenic acid) was also reversed by paliperidone. MIA induces specific long-term brain effects on serotonergic activity. Such effects seem to be related with alternative activation of the kynurenine metabolic pathway towards a cytotoxic status. Atypical antipsychotic paliperodine partially remediates abnormalities observed after MIA.Instituto de Salud Carlos IIISpanish Ministry of Economy and CompetivenessCIBERSAMBasque GovernmentDepto. de Farmacología y ToxicologíaFac. de MedicinaTRUEpu

Expression of aquaporin 4 (AQP4) in postmortem human brain cortex of subjects with different psychiatric disorders

Trabajo presentado al 39th annual meeting of Neuroscience celebrado en Chicago del 17 al 21 de octubre de 2009.Aquaporins are specialized water transport channels expressed in plasma membranes of water-permeable tissues that maintain water and ion homeostasis. Aquaporins 1 and 4 (AQP1 and AQP4) are the most important to fluid movements in mammalian brain. AQP4 has been implicated in the generation of brain edema, astrocyte migration, and in the control of neuronal excitability. These and other studies have turned it into an important drug target for treatment of diseases such as cerebral edema, mesial temporal lobe epilepsy, and a variant of multiple sclerosis. Moreover, over-expression changes of the gene coding for the AQP4 have been associated with bipolar disorder and major depression, and it has been described as necessary for the antidepressive action of fluoxetine. The aim of this study was to evaluate the immunoreactive protein density of AQP4 in postmortem prefrontal cortex samples of subjects with a previous diagnosis of three different mental disorders: major depression (MD, n=15), bipolar disorder (BD, n=19) and schizophrenia (SCH, n=22). Three groups of matched controls for gender, age and postmortem delay were included. Additionally, a group of suicide victims (n=12) with no previous diagnosis of mental disorder was also included. The immunodensities of the two isoforms of AQP4 (34 and 32 kDa) and beta-actin (used as internal control) were detected simultaneously by using specific primary and fluorescent secondary antibodies. The density of AQP1 was also quantified. All bands were quantified by densitometry and the relative density levels were normalized and expressed as a percentage of control samples. An increase of the density of the two AQP4 isoforms was detected in MD, BD, and SCH groups, while no changes were detected in the case of suicide. These changes were statistically significant for both the 32 and 34 kDa isoforms in BD (34 kDa: 118%, p0.05) in SCH and suicide (91%, p>0.05) groups. These results suggests an implication of aquaporins in neuropsychiatric disorders.Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM; MICINN (SAF 2004/2784); MICINN (FIS 04/0190) and FEDER Funds.Peer Reviewe

Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- et al.Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.The study was supported by an intramural Grant from Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III (CIBERSAM), Spanish MICINN and FEDER (SAF2009-08460 to JJM; SAF2010-21948 to JLMMM; AGL2009-11358 to AG-A, SAF2011-29918 to JAGS; PI10/02986, CP08/00017 and CEN-20101014 to MD), Basque Government (S-PR10UN01 to JEO and IT-199/07 to JJM), University of the Basque Country (UPV/EHU) and Complutense University of Madrid (UCM GR42/10-962075 to JLMM).Peer Reviewe

Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D-1 receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia.Brainco Biopharma SL; Centro de Investigacion Biomedica en Red de Salud Mental; Instituto de Salud Carlos III (CIBERSAM); Spanish MICINN; FEDER SAF2009-08460, SAF2010-21948,AGL2009-11358, SAF2011-29918, PI10/02986, CP08/00017,CEN-20101014; Basque Government PR10UN01 IT-199/07; University of the Basque Country (UPV/EHU); Complutense University of Madrid UCM GR42/10-96207