香京julia种子在线播放

Schizophrenia is a mental disease that affects approximately 1% of the population. Its symptoms are hallucination, delusions, thought disorder, flat affect, social withdrawal, and cognitive disorder. Genetic and environmental factors are involved in schizophrenia, although its detailed mechanisms are not fully understood. Drugs with antagonistic potency against dopamine D₂ receptors are widely used for treating schizophrenia. These antagonists effectively manage the abnormal behavior, and thus dysfunction of midbrain dopamine transmission is generally accepted to underlie the symptoms of schizophrenia. Further studies have shown involvement of L-Glu-mediated excitatory transmission in schizophrenia pathogenesis (Coyle, 2006; Laruelle, 2014). In experimental animals, N-methyl-D-aspartate (NMDA) receptor antagonists cause schizophrenia-like behavioral abnormalities, accompanied by dopamine system hyperactivation (Lipina et al., 2005; Karasawa et al., 2008; Bado et al., 2011; Kawaura et al., 2014). Moreover, administration of NMDA antagonists to schizophrenic patients aggravates their symptoms (Javitt and Zukin, 1991; Krystal et al., 1994), suggesting that inhibition of NMDA receptor-mediated transmission facilitates induction of schizophrenia. NMDA receptors have an allosteric site that regulates L-Glu-mediated receptor activation. D-serine is a necessary co-factor for NMDA receptor/channel gating, and enhances the excitatory signal (Balu et al., 2012; Van Horn et al., 2013). The D-Ser biosynthetic enzyme, serine racemase (SR), and D-Ser degradation enzyme, D-amino acid oxidase (DAAO), are both present in brain regions with high NMDA receptor expression (Van Horn et al., 2013). Immunohistochemical observations show that SR locates to astrocytes (Wolosker et al., 1999; Panatier et al., 2006), while D-Ser release from astrocytes is stimulated by excitatory amino acids (Martineau et al., 2014), indicating that D-Ser serves as a gliotransmitter. In schizophrenia patients, D-Ser levels are decreased in cerebrospinal fluid (Hashimoto et al., 2003; Bendikov et al., 2007), whereas DAAO protein and its activity are increased in the hippocampus and cerebrum (Madeira et al., 2008; Habl et al., 2009). Human genetic analysis shows that several polymorphic variants of SR and DAAO are related to increased risk of schizophrenia (Labrie et al., 2009; Caldinelli et al., 2013). Concurrent with these observations, manipulation of brain D-Ser levels induces schizophrenia-like behavior in experimental animals. Basu et al. (2009) reported that genetic deletion of SR causes hyperactivity and impaired memory in mice, accompanied by altered NMDA responses. Further observations of the SR null mouse found morphological and neurochemical abnormalities in the brain, similar to those in schizophrenia (Puhl et al., 2014). In contrast, DAAO deletion reverses schizophrenia-like abnormal behavior in mice with impaired NMDA receptor function (Labrie et al., 2010). The effect of D-Ser and related drugs has been examined in animal models of schizophrenia. Administration of D-Ser, D-Ser reuptake inhibitors (ALX5407 and (R)-(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl] sarcosine (NFPS)) and DAAO inhibitors ([4H-thieno [3, 2-b]pyrrole-5-carboxylic acid] (compound 8), 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and AS057278) improve impaired pre-pulse inhibition and cognitive defects induced by NMDA antagonists (Lipina et al., 2005; Adage et al., 2008; Karasawa et al., 2008; Hashimoto et al., 2009; Smith et al., 2009; Bado et al., 2011; Kawaura et al., 2014). Therapeutic effects of D-Ser and glycine on negative symptoms of schizophrenia patients have been reported, and more effective drugs for enhancing NMDA receptor signaling should be explored (Tuominen et al., 2005; Tsai and Lin, 2010). Currently, atypical antipsychotics, which improve both positive and negative symptoms, are used for the treatment of schizophrenia. Some atypical antipsychotics (clozapine, olanzapine, and risperidone), but not haloperidol, enhance L-Glu transmission in the prefrontal cortex via NMDA receptors (Ninan et al., 2003; Kargieman et al., 2007). Recently, Tanahashi et al. (2012) showed that clozapine, but not haloperidol, stimulates D-Ser release from astrocytes, suggesting a novel mechanism of atypical antipsychotics in schizophrenia treatment.

Among the mood disorders, morphological and functional alterations of astrocytes are apparent in patients with MDD (Sanacora and Banasr, 2013). Postmortem brain examination of MDD patients shows decreased astrocyte cell number and GFAP protein in the hippocampus (Stockmeier et al., 2004), frontal cortex (Ongür et al., 1998; Cotter et al., 2002), and amygdala (Hamidi et al., 2004). Decreased astrocyte cell number and GFAP protein are reproduced in animal models subjected to chronic unpredictable stress (Heine et al., 2004; Czéh et al., 2006). Administration of L-α-aminoadipate (an astrogliotoxin used as a tool to induce specific astrocytic degeneration) into the rat prefrontal cortex causes depressive-like behavior (Banasr and Duman, 2008). Based on these findings, possible involvement of impaired astrocyte function in the pathogenesis of depression has been investigated. While therapeutic mechanisms of clinically used antidepressants can be explained by the “monoamine hypothesis”, L-Glu transmission has also been considered as a therapeutic target for depression. In rat social interaction and sucrose intake tests, administration of L-Glu transport inhibitors leads to depressive-like behavior (Lee et al., 2007; John et al., 2012), suggesting that impaired L-Glu turnover between astrocytes and neurons causes depression. As well as GFAP, expressions of astrocyte-specific molecules (e.g., EAAT-1, EAAT-2, and GS) are decreased in MDD, along with the reduction in astrocyte cell number (Choudary et al., 2005). As EAAT-1 and EAAT-2 are the main uptake pathways for extracellular L-Glu into astrocytes, decreased EAAT-1 and EAAT-2 expression may cause impaired L-Glu turnover and result in depression. Involvement of impaired L-Glu turnover in depression pathogenesis is supported by the beneficial effect of riluzole in animal models of depression. Riluzole, which is clinically used for ALS treatment, activates L-Glu transporters (Fumagalli et al., 2008). Furthermore, Banasr et al. (2010) found that riluzole reverses decreased GFAP expression in the rat prefrontal cortex and improves depressive-like behavior after chronic unpredicted stress. Although the mechanisms underlying morphological and functional alterations of astrocytes remain to be clarified, the beneficial action of riluzole suggests that modulating L-Glu turnover in astrocytes is a novel strategy for treatment of depression.

Neuronal and glial cell genesis is not limited to the developing brain and can occur in restricted areas of the adult brain, mainly the hippocampus and sub-ventricular zone (SVZ). Many studies have attempted to show correlation between the pathology of neurological disorders and deregulation of cellular genesis in the adult brain. Reduced hippocampal neurogenesis is implicated in the pathogenesis of depression, and as a possible target of antidepressants (Santarelli et al., 2003; Banasr and Duman, 2007). Moreover, recent animal model studies implicate astrogliogenesis in depression pathogenesis. Olfactory bulb dissection can induce depressive-like behavioral changes in rats. Keilhoff et al. (2006) showed that olfactory bulb dissection decreases neural precursor proliferation in the hippocampus and SVZ, which can be rescued by the antidepressant, imipramine. Similarly, chronic social stress decreases astrocyte number and cell volume in the rat hippocampus, which can be reversed by fluoxetine (Czéh et al., 2006). In contrast, electroconvulsive seizures, an effective treatment for severe depression, stimulates astrocyte proliferation in the rat hippocampus and prefrontal cortex (Ongür et al., 2007; Jansson et al., 2009). These findings support the involvement of astrogliogenesis in the pathogenesis of depression. Recently, Kong et al. (2014) found that deletion of AQP4, a water channel protein expressed in astrocytes, aggravates depressive-like behavior and is accompanied by a further reduction in astrocyte cell number and hippocampal neurogenesis. This suggests that astrocytic AQP4 may be a novel target for antidepressants.

Increased production of neurotrophic factors is predicted to be an effective treatment strategy for mood disorders, because they promote neurogenesis, gliogenesis, and synaptic structure remodeling. Levels of BDNF (Dwivedi et al., 2003), GDNF (Otsuki et al., 2008; Zhang et al., 2008), and basic fibroblast growth factor (bFGF; Evans et al., 2004) are decreased in patients with depression, and relates to the reduced hippocampal neurogenesis. Astrocytes are a main source of these neurotrophic factors in pathological brain conditions (Koyama et al., 2003). Administration of antidepressants (e.g., desipramine, fluoxetine, mianserin, clomipramine, and paroxetine) increases production of BDNF, GDNF, and bFGF in the rat hippocampus (Mallei et al., 2002; Martínez-Turrillas et al., 2005; Bachis et al., 2008; Liu et al., 2012), while in vitro studies using cultured astrocytes treated with antidepressants shows production of these neurotrophic factors (Hisaoka et al., 2001; Allaman et al., 2011; Kittel-Schneider et al., 2012). Thus, up-regulation of astrocytic trophic factor production may partially underlie the therapeutic actions of presently used antidepressants.

A relationship between CX43, a main component of astrocytic gap junctions, and MDD has been suggested. Reduced brain CX43 expression is observed in MDD patients (Bernard et al., 2011; Miguel-Hidalgo et al., 2014). Inhibition of CX43-mediated gap junction communication causes depressive-like behavior in rodents (Sun et al., 2012). Besides neurotrophic factor production, increased CX43 expression is proposed as a novel mechanism for clinically used antidepressants. Sun et al. (2012) found that fluoxetine and duloxetine increase CX43 expression in rat brain. Moreover, amitriptyline increases CX43 expression by a monoamine-independent mechanism in cultured astrocytes (Morioka et al., 2014).

Repeated abuse of opiates, hypnotics, and psychostimulants leads to drug dependence. It is known that drug-induced alterations in synaptic strength in the mesocorticolimbic dopamine system and modulatory glutamatergic neuronal circuits, both part of the brain reward system, underlie drug dependence (van Huijstee and Mansvelder, 2015). Dependence-producing drugs commonly activate the main pathway of the brain reward system, with dopamine released from neurons in the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) and prefrontal cortex. Studies on the mechanisms underlying drug dependence show a possible role for astrocytes in modulating neurotransmission in the brain reward system (Beardsley and Hauser, 2014). Administration of amphetamine, methamphetamine, cocaine, and morphine induces astrocyte activation and increases GFAP expression in rodent brain (Hebert and O’Callaghan, 2000; Fattore et al., 2002; Pubill et al., 2003; Alonso et al., 2007). Although these astrocytic alterations are not necessarily a common pathological feature shared by other drugs, these observations facilitate examination of the mechanisms underlying drug dependence in the context of astrocyte function.

The L-Glu-mediated neural circuit from the prefrontal cortex to NAcc plays an important regulatory role in the brain reward system (van Huijstee and Mansvelder, 2015). Nakagawa et al. (2005) examined the role of astrocytic L-Glu transporters in mice by co-administrating MS-153, a glutamate transport activator, with morphine, cocaine, or methamphetamine. They found that activation of L-Glu transport attenuates conditioned place preference (CPP) to these drugs. Administration of an adenoviral vector carrying the glutamate transporter 1 (GLT1; EAAT-2) gene into the NAcc also attenuated CPP induction by morphine and methamphetamine (Fujio et al., 2005). Together, these findings suggest there is inhibitory regulation from astrocytic L-Glu transporters on the rewarding effect of dependence-producing drugs.

Astrocyte-derived soluble factors have important roles in regulating synaptic strength and plasticity. The effect of astrocyte-derived factors on susceptibility to drug dependence was examined using conditioned medium from cultured astrocytes. Administration of astrocytic conditioned medium into mouse NAcc caused sensitization of rewarding behavior elicited by methamphetamine and morphine (Narita et al., 2005, 2006), suggesting that astrocytes produce soluble factors that enhance drug dependence. As astrocyte-derived factors affect susceptibility of drug-dependence, the modulatory roles of BDNF and GDNF on rewarding effects of psychostimulants were examined (Ghitza et al., 2010). Enhancement of a rewarding effect by BDNF was first shown by Horger et al. (1999), with chronic BDNF administration into rat NAcc increasing CPP to cocaine. Overexpression of exogenous BDNF and its receptor (TrkB) in rat NAcc also increased CPP to cocaine (Bahi et al., 2008), while mouse BDNF null mutants show reduced CPP (Hall et al., 2003). Positive regulatory roles of BDNF were also suggested from the rewarding effects of morphine and amphetamine (Shen et al., 2006; Vargas-Perez et al., 2009). As had been predicted from animal experiments (Pu et al., 2006; Hatami et al., 2007), a recent study showed that serum BDNF levels in heroin-dependent patients are still higher than those of control groups, even after drug withdrawal (Zhang et al., 2014). The results from viral vector-mediated gene transfer experiments in rodents (Vargas-Perez et al., 2014) propose that enhancement of the BDNF signal in the VTA is related to drug withdrawal aversion.

GDNF was originally discovered as a survival and developmental factor for mesencephalon dopaminergic neurons, and modulates nerve excitation in many brain regions, including the VTA and NAcc (Carnicella and Ron, 2009). In contrast to BDNF, GDNF serves as a negative reinforcement modulator of the rewarding effects of psychostimulants. Administration of GDNF into the rat VTA reduced CPP enhancement to cocaine, while an anti-GDNF neutralizing antibody increased it (Messer et al., 2000). Heterozygous GDNF deletion in mice caused higher sensitivity in CPP and seeking behaviors to methamphetamine than those of wild-type mice (Niwa et al., 2007; Yan et al., 2007). Taking these observations into consideration, a therapeutic effect for drugs enhancing GDNF production in patients with psychostimulant dependence can be expected. Cabergoline, a dopamine D₂ agonist used for the treatment of hyperprolactinemia and parkinsonism, increases GDNF production in cultured astrocytes (Ohta et al., 2003, 2004) and rat VTA (Carnicella et al., 2009). Cabergoline-induced GDNF production in rat VTA reduced reinforcement of seeking and drinking behavior for alcohol (Carnicella et al., 2009).

Dysplasia of nerve tissue during embryonic and postnatal development underlies some neurological diseases with mental retardation and cognitive defects. During development of the embryonic brain, astrocytes support proliferation and migration of neural precursors, neuronal differentiation, and synaptic formation, although neurogenesis generally precedes maturation of astrocytes from glial precursors (Freeman and Rowitch, 2013). Because of the important role of astrocytes in the developing brain, investigations to explain the etiology of neurodevelopmental diseases by astrocyte dysfunction have been performed (Molofsky et al., 2012; Parpura et al., 2012). A number of studies on two inherited developmental diseases with mental retardation, Rett syndrome and FXS, show that mutations in single genes are responsible for astrocyte dysfunction and impaired brain development.

Rett syndrome, an X-linked neurological disease characterized clinically by distinctive hand movements, seizures, delayed brain and head growth, autism, and mental retardation (Weng et al., 2011), is caused by mutations in a transcription factor, methyl-CpG-binding protein 2 (MeCP2; Samaco and Neul, 2011). In studies using MeCP2 null mutant mice as a model of Rett syndrome (Chen et al., 2001), conditional MeCP2 expression in postnatal neurons partly reversed behavioral abnormalities (Giacometti et al., 2007; Guy et al., 2007), indicating involvement of reduced neural MeCP2 in pathogenesis of the model. In addition, reduced function of astrocytic MeCP2 is also related to Rett syndrome pathogenesis. In vitro experiments by Ballas et al. (2009) found that hippocampal neurons cultured with MeCP2 deleted astrocytes or their conditioned medium, failed to show normal dendritic development. Impaired dendrite formation by astrocytic MeCP2 occurs independent of the presence of neural MeCP2, suggesting that dysregulation of astrocytic soluble factors induced by MeCP2 deletion may relate to induction of Rett syndrome-like phenotypes. Maezawa et al. (2009) reported impairments in BDNF, interleukin-1β, and interleukin-6 production in astrocytes from MeCP2 deleted mutant mice.

FXS is a neurodevelopmental disease characterized by mental retardation, autism, attention deficit, social anxiety, and specific physical features. One of the genes responsible for FXS, fragile X mental retardation 1 (FMR1), is on an X-linked chromosome. Mutations in FMR1, with GCC expansions repeats in the promoter region, decrease production of fragile X mental retardation 1 protein (FMRP), which serves as a regulator of local protein translation. Reduced FMRP activity in neurons leads to dysregulation of synaptic protein expression and affects dendrite formation (Bassell and Warren, 2008). FMR1 gene deletion induces abnormal dendrite elongation and increases spine density in the developing cerebral cortex (Comery et al., 1997; Nimchinsky et al., 2001). Besides neuronal reduction, reduced FMRP activity in astrocytes affects their function during brain development (Jacobs and Doering, 2010; Jacobs et al., 2010). The mechanisms by which reduced FMRP in astrocytes induces abnormal dendrite development were investigated. Yang et al. (2012) found that FMRP deletion increases neurotrophin-3 production in astrocytes, which suggests that excess neurotrophic actions underlie abnormalities in dendrite development. The metabotropic glutamate receptor 5 (mGluR5) is predicted to be a therapeutic drug target for FXS (Levenga et al., 2011; Vinueza Veloz et al., 2012; Pop et al., 2014; Scharf et al., 2015). Higashimori et al. (2013) proposed that down-regulation of astrocytic mGluR5 and GLT-1 (EAAT-2) by FMRP deletion may cause enhanced neuronal excitation and lead to abnormal dendritic development in FXS mouse models.