Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid
Introduction
Schizophrenia is a mental disorder, usually emerging in adolescence or early adulthood (Andreasen, 1995) and is characterized by a large diversity of positive and negative symptoms as well as cognitive deficits. Aberrations in brain dopamine (DA) neurotransmission as part of the pathophysiology has for long been the predominant biological hypothesis of schizophrenia (Carlsson and Lindqvist, 1963, Carlsson and Carlsson, 2006). The DA hypothesis arises from the finding of amelioration in positive symptoms following blockade of DA D2-receptors, as well as from observations of psychosis following frequent abuse of the indirect DA agonist d-amphetamine (Angrist and Gershon, 1970, Cruickshank and Dyer, 2009, Griffith et al., 1972). Further supporting the DA hypothesis, brain imaging studies reveal an enhanced DA release following administration of d-amphetamine in patients with schizophrenia (Abi-Dargham et al., 1998, Breier et al., 1997, Laruelle et al., 1996). Research during the last decade however, proposes that DA only plays an intermediary role in the pathophysiology and that deficits in brain glutamatergic systems are of major importance for the disease (Carlsson et al., 2001, Javitt, 2004, Jentsch and Roth, 1999). For example, administration of N-methyl-d-aspartic acid (NMDA) receptor antagonists (e.g. phencyclidine and ketamine) evokes behavior similar to schizophrenia symptoms in healthy individuals, and exacerbates symptoms in patients with schizophrenia (Adler et al., 1999, Javitt and Zukin, 1991, Luby et al., 1959). Providing strong support for a dysfunction of glutamatergic transmission in schizophrenia, the concentration of kynurenic acid (KYNA) is elevated in the cerebrospinal fluid (CSF) and in post mortem brain of patients with schizophrenia (Erhardt et al., 2001a, Linderholm et al., 2012, Nilsson et al., 2005, Sathyasaikumar et al., 2011, Schwarcz et al., 2001). KYNA is a tryptophan metabolite, synthesized in astrocytes via the kynurenine pathway. At nanomolar concentrations, KYNA antagonizes the glycine-site of the NMDA receptor as well as the cholinergic α7 nicotinic receptor (α7nAChR; Schwarzc et al., 2012). At higher, micromolar concentrations, KYNA blocks the glutamate recognition-site of the NMDA receptor (Kessler et al., 1989). Notably, endogenous concentrations of KYNA tonically control DA transmission in the rat brain (Erhardt et al., 2009, Linderholm et al., 2007, Amori et al., 2009b, Schwieler et al., 2008), findings functionally linking the DA hypothesis to the glutamate deficiency theory of schizophrenia.
Synthesis of KYNA is induced following immune activation (Dantzer et al., 2008). Indeed, CSF KYNA is elevated in various infectious diseases (Heyes et al., 1992), such as those caused by human immunodeficiency virus-1 or tick-borne encephalitis (Atlas et al., 2007, Holtze et al., 2012) or during influenza A virus infections of neuron or glial cultures in vitro (Holtze et al., 2008). Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), the initial and rate-limiting enzymes in the production of KYNA, are induced by interferon-γ or other pro-inflammatory cytokines (Schwarcz et al., 2012) and are important in controlling microbial growth as well as the host immune response (King and Thomas, 2007). Moreover, activation of the pro-inflammatory cytokine interleukin (IL)-1β in CSF from first-episode patients with schizophrenia was recently reported, strongly indicating immune dysregulation in the disease (Soderlund et al., 2009). Interestingly, exposure to infections, including influenza A virus, during early-life appear to increase the risk for the future development of schizophrenia and related psychotic disorders (Blomström et al., 2012, Brown and Derkits, 2010, Dalman et al., 2008, Ellman et al., 2009, Yolken and Torrey, 2008). While a causal link between early-life exposure to infections and the later development of psychoses is still missing, several animal studies have demonstrated deficits in prepulse inhibition (PPI), a cross-species measure of sensorimotor gating which is impaired in patients with schizophrenia (Braff et al., 2001), in adult animals following either prenatal or early-life exposure to immunostimulatory agents (Crnic and Pizer, 1988, Engel et al., 2000, Gold et al., 1994, Meyer and Feldon, 2010, Tohmi et al., 2004). We recently reported that a neonatal infection with neurotropic influenza A/WSN/33 virus transiently increases brain KYNA concentrations in wild type mice as well as in immunodeficient mice with a targeted disruption of the gene-encoding transporter associated with antigen processing 1 (Tap1−/−), leading to a lack of MHC class I expression and functional CD8+ T cells (Asp et al., 2010, Holtze et al., 2008). The neonatal infection was associated with deficits in PPI and working memory as well as with increased rearing and anxiety in adult immunodeficient mice, but not in adult wild type mice (Asp et al., 2009, Asp et al., 2010). A recent study from our laboratory also shows that mice with subchronically elevated levels of KYNA in adulthood have normal spontaneous locomotor activity but a potentiated locomotor response to d-amphetamine (Olsson et al., 2012a). Since our previous studies showed that wild type mice neonatally infected with influenza A virus do not show aberrant behavior under baseline conditions, in the present study we investigated the locomotor response to challenge with d-amphetamine. A second aim of the present study was to investigate whether neonatally elevated brain KYNA is associated with the disturbed behavior in adulthood seen after infection in early life.
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Animals
C57BL/6 mice were used for all experiments. Pregnant mice were obtained from Scanbur AB, Sweden and kept in a single cage until delivery. All pups (males and females) stayed with their mothers until weaning (5–8 mice per cage). After weaning at the age of four weeks, all mice were group-housed in standard transparent cages (2–5 mice per cage, as determined by the number of male mice in each litter) because isolation rearing (i.e. housing mice one per cage) can affect amount of PPI and locomotor
Locomotor activity assessed in the open field following virus infection
Basal horizontal activity in adult animals did not differ between neonatally influenza A/WSN/33 virus infected mice (n = 16) and their uninfected controls (n = 17; Fig. 2). Acute administration of d-amphetamine (5 mg/kg, i.p.) in adult life increased horizontal activity in neonatally influenza A/WSN/33 virus-infected mice (n = 8) and in uninfected controls (n = 9). As compared to the uninfected control mice, neonatally influenza A virus-infected mice showed a more pronounced increase in
Discussion
The present study shows that a neonatal infection with a neurotropic mouse-adapted strain of influenza A virus is associated with enhanced responsiveness to d-amphetamine in adult animals, as measured in the open field. Similarly, neonatal administration of l-kynurenine, leading to elevated brain levels of endogenous KYNA during treatment, enhanced the locomotor responsiveness to d-amphetamine in adult mice. d-Amphetamine administration also tended to potentiate DA release in the striatum of
Conflict of interest statement
All authors declare that there are no conflicts of interest.
Acknowledgements
Financial support for this study was provided by Petrus och Augusta Hedlunds Stiftelse, the Swedish Research Council (Dr. Erhardt, No. 2009-7052; 2011-4795, Dr. Engberg, No 2008-3822-; 2009-3068, Dr. Karlsson K2009-61X-20047-04-3), The European Society of Anaesthesiology (Dr. Terrando), the Karolinska Institutet, (KID) Karolinska Institutets stiftelse för virus forskning, Stiftelsen Sigurd och Elsa Golje Minne, Svenska Läkaresällskapet, Åhléns-stiftelsen, MH091407 (SBP), the Stanley Medical
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These authors contributed equally.