Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology?

Probably not a substantial claim: may not pass S3 (load-bearing).

Parvalbumin interneurons are GABAergic neurons that form inhibitory synapses onto either the cell body or the axon initial segment of pyramidal neurons.

“PVI are GABAergic neurons that form inhibitory synapses onto either the cell body (for parvalbumin-expressing basket cells) or the axon initial segment (for parvalbumin-expressing chandelier cells) of pyramidal neurons (PNs).”

May combine two claims.

Parvalbumin interneurons are critical for high-frequency neuronal synchrony reflected in gamma band oscillations and can also modulate theta band activity and theta-gamma coupling.

“They are critical for high-frequency neuronal synchrony, reflected in gamma band oscillations (30–80 Hz) (Cardin et al., 2009; Fuchs et al., 2007; Gulyas et al., 2010; Massi et al., 2012; Sohal et al., 2009), but can also modulate neuronal activity in the theta band (4–8 Hz), as well as theta-gamma coupling (Korotkova et al., 2010; Wulff et al., 2009).”

• cites Cardin et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Korotkova et al., 2010Not checked yet

  Not checked in the free run.

• cites Wulff et al., 2009Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S2 (checkable).

The primary effector system may depend on the specific combination of genetic vulnerability and environmental insults.

“To our view, the primary effector may depend on the specific combination of the genetic vulnerability and environmental insults.”

Probably not a substantial claim: may not pass S4 (based).

Diverse genetic vulnerabilities and environmental risk factors may affect one element of the redox-immune-glutamatergic triad, impacting the other systems in turn.

“Diverse genetic vulnerabilities and environmental risk factors may affect one element of this triad, impacting in turn the other systems.”

May combine two claims.

Dysregulation of redox, neuroimmune, and glutamatergic systems caused by genetic and early-life environmental risk factors could contribute to parvalbumin interneuron and white matter anomalies in schizophrenia, affecting cognition, social competence, and affective behavior through abnormal micro- and macrocircuits.

“These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits.”

May combine two claims.

Many inflammatory mediators are activated by oxidative molecules, and activated immune cells such as microglia generate reactive oxygen and nitrogen species.

“Many inflammatory mediators are activated by oxidative molecules, while activated immune cells such as microglia generate ROS and RNS.”

May combine two claims.

Anomalies associated with parvalbumin interneurons are a hallmark of schizophrenia, including reduced density of parvalbumin-immunoreactive cells in the hippocampal formation and alterations in basket and chandelier cells in the dorsolateral prefrontal cortex of post-mortem brains.

“Anomalies associated with PVI constitute a hallmark of the disease, including reduced density of parvalbumin-immunoreactive cells in the hippocampal formation (Wang et al., 2011; Zhang and Reynolds, 2002) and alterations at the level of basket and chandelier cells in the dorsolateral prefrontal cortex (DLPFC) of post-mortem brains (Lewis et al., 2012).”

• cites Wang et al., 2011Not checked yet

  Not checked in the free run.

• cites Zhang and Reynolds, 2002 sourceNot checked yet

  Not checked in the free run.

• cites Lewis et al., 2012 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Redox signaling plays a key regulating role in many cellular and physiological processes.

“In addition, redox signaling plays a key regulating role in many cellular and physiological processes (Jones, 2008).”

• cites Jones, 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Redox state modulates NMDAR function, while activation of synaptic NMDARs strengthens neuronal antioxidant defense mechanisms.

“While redox state modulates NMDAR function, activation of synaptic NMDARs strengthens neuronal antioxidant defense mechanisms (Hardingham and Bading, 2010).”

• cites Hardingham and Bading, 2010 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Dysfunction in the redox, neuroimmune, and glutamatergic systems has deleterious effects on normal development of cortical and hippocampal parvalbumin-expressing interneurons and on oligodendrocytes.

“In particular, we propose that dysfunction in these systems has deleterious effects on normal development of cortical and hippocampal parvalbumin-expressing interneurons (PVI), which are essential for fast local neuronal synchronization, and on oligodendrocytes, which form myelin sheets around axons providing fast signal conduction between brain regions.”

May combine two claims.

In prefrontal cortical regions, parvalbumin interneurons mature during adolescence, and this protracted developmental trajectory could explain the peri-adolescent onset of schizophrenia symptoms.

“Furthermore, in prefrontal cortical regions, heavily implicated in schizophrenia pathophysiology, PVI mature during adolescence (Tseng and O’Donnell, 2007; O’Donnell, 2011) and is therefore a neural population with a protracted developmental trajectory that could explain the peri-adolescent onset of schizophrenia symptoms.”

• cites Tseng and O’Donnell, 2007Not checked yet

  Not checked in the free run.

• cites O’Donnell, 2011Not checked yet

  Not checked in the free run.

May combine two claims.

Schizophrenia is characterized by altered GABAergic parvalbumin-expressing interneurons and impaired myelin or axonal integrity.

“Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia.”

May combine two claims.

Human subjects with anti-NMDAR encephalitis develop psychosis, and antibodies against NMDAR have been reported in patients diagnosed with schizophrenia.

“Human subjects with anti-NMDAR encephalitis develop psychosis (Dalmau et al., 2011) and antibodies against NMDAR have been reported in patients diagnosed with schizophrenia (Steiner et al., 2013).”

• cites Dalmau et al., 2011Not checked yet

  Not checked in the free run.

• cites Steiner et al., 2013Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Anomalies of parvalbumin interneurons and oligodendrocytes are widely recognized in schizophrenia and are considered to contribute to abnormal brain connectivity leading to cognitive, affective, and social deficits.

“Anomalies of PVI and oligodendrocytes are indeed widely recognized in schizophrenia and considered to contribute to abnormal brain connectivity leading to cognitive, affective, and social deficits.”

May combine two claims.

Postnatal deletion of the NR1 subunit of NMDARs in a subpopulation of interneurons including most parvalbumin interneurons leads to parvalbumin and GAD67 expression deficits along with oxidative stress in parvalbumin interneurons.

“When applied during postnatal development, a deletion of the NR1 subunit of NMDARs in a subpopulation of interneurons (including most PVI) leads to parvalbumin and GAD67 expression deficit along with oxidative stress in PVI (Belforte et al., 2010; Jiang et al., 2013).”

• cites Belforte et al., 2010 sourceNot checked yet

  Not checked in the free run.

• cites Jiang et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

The neonatal ventral hippocampal lesion model displays oxidative stress and a parvalbumin interneuron defect, both of which are prevented by juvenile and adolescent treatment with N-acetylcysteine.

“First, the widely studied neonatal ventral hippocampal lesion model also displays oxidative stress and PVI defect, both of which are prevented by a juvenile and adolescence treatment with the antioxidant and GSH precursor, N-acetylcysteine (NAC) (O’Donnell et al., 2011; Sullivan and O’Donnell, 2012).”

• cites O’Donnell et al., 2011Not checked yet

  Not checked in the free run.

• cites Sullivan and O’Donnell, 2012Not checked yet

  Not checked in the free run.

May combine two claims.

The dorsolateral prefrontal cortex of young patients already has low expression levels of parvalbumin and GAD67, and the gene expression pattern in parvalbumin interneurons of schizophrenia individuals resembles that of non-mature cells.

“The DLPFC of young patients already has low expression levels of parvalbumin and GAD67 (Hoftman et al., 2013), and gene expression pattern in PVI of schizophrenia individuals resembles that of non-mature cells (Gandal et al., 2012).”

• cites Hoftman et al., 2013Not checked yet

  Not checked in the free run.

• cites Gandal et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Developmental insults in animal models cause oxidative stress and/or neuroinflammation.

“These developmental insults cause oxidative stress (Do et al., 2009b; Walter et al., 2002) and/or neuroinflammation (Brenhouse and Andersen, 2011; Garate et al., 2013; Kaur et al., 2013).”

• cites Do et al., 2009bNot checked yet

  Not checked in the free run.

• cites Walter et al., 2002Not checked yet

  Not checked in the free run.

• cites Brenhouse and Andersen, 2011Not checked yet

  Not checked in the free run.

May combine two claims.

Inhibition of NMDARs during early life causes a persistent decrease in the number of parvalbumin-immunoreactive cells without cell death, suggesting that disruption of NMDAR-mediated signaling impairs maturation of these cells.

“Inhibition of NMDARs during early life causes a persistent decrease in number of parvalbumin-immunoreactive cells without cell death (Powell et al., 2012), suggesting that disruption of NMDAR-mediated signaling impairs maturation of these cells.”

• cites Powell et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In an animal model with low glutathione content, as reported in the brain of some schizophrenia patients, there is a deficit in prefrontal and hippocampal parvalbumin interneurons, impairing high-frequency neuronal synchronization.

“In an animal model with low GSH content, as reported in the brain of some schizophrenia patients (Do et al., 2000; Gawryluk et al., 2011; Yao et al., 2006), there is a deficit in prefrontal and hippocampal PVI, impairing high-frequency neuronal synchronization (Cabungcal et al., 2013a; Cabungcal et al., 2013b; Steullet et al., 2010).”

• cites Do et al., 2000Not checked yet

  Not checked in the free run.

• cites Gawryluk et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites Yao et al., 2006 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Interneuron dysfunction could contribute to altered sensory perception and deficits in working memory, attention, and learning.

“Ultimately, interneuron dysfunction could contribute to altered sensory perception (Atallah et al., 2012), deficits in working memory (Korotkova et al., 2010; Roux et al., 2012), attention (Rouhinen et al., 2013), and learning (Carlen et al., 2012).”

• cites Atallah et al., 2012 sourceNot checked yet

  Not checked in the free run.

• cites Korotkova et al., 2010Not checked yet

  Not checked in the free run.

• cites Carlen et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

NMDAR blockade in adults disrupts excitatory/inhibitory balance in cortical circuits, affecting parvalbumin interneurons and neuronal network activity.

“Numerous studies show that NMDAR blockade in adults disrupts excitatory/inhibitory balance in cortical circuits, affecting PVI (Behrens et al., 2007) and neuronal network activity (Carlen et al., 2012; Homayoun and Moghaddam, 2007; Kocsis et al., 2013; Korotkova et al., 2010; Lazarewicz et al., 2010).”

• cites Behrens et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Carlen et al., 2012Not checked yet

  Not checked in the free run.

• cites Homayoun and Moghaddam, 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Superoxide overproduction by NADPH oxidase is deleterious to parvalbumin interneurons, and NOX inhibition prevents the parvalbumin interneuron impairment induced by social isolation.

“Furthermore, superoxide overproduction by NADPH oxidase (NOX) is also deleterious to PVI (Behrens et al., 2007), and NOX inhibition prevents the PVI impairment induced by social isolation (Schiavone et al., 2009).”

• cites Behrens et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Schiavone et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The maturation of parvalbumin interneurons is activity-dependent; calcium entry is necessary for maturation of perineuronal nets and parvalbumin interneurons, and activation of NR2A-containing NMDARs contributes to the molecular signaling that leads to maturation of these cells.

“Indeed, the maturation of PVI is activity-dependent (Chattopadhyaya et al., 2004; Patz et al., 2004). Calcium entrance is necessary for the maturation of PNN (Dityatev et al., 2007) and PVI (Jiang and Swann, 2005; Kinney et al., 2006), and activation of NR2A-containing NMDARs contributes to the molecular signaling that leads to the maturation of these cells (Kinney et al., 2006; Zhang and Sun, 201”

• cites Chattopadhyaya et al., 2004 sourceNot checked yet

  Not checked in the free run.

• cites Patz et al., 2004Not checked yet

  Not checked in the free run.

• cites Kinney et al., 2006 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Methylazoxymethanol acetate treatment during pregnancy causes schizophrenia phenotypes in adult rats and leads to anomalies in parvalbumin interneurons and neuronal synchronization; MAM-treated rats also have decreased brain glutathione levels.

“Second, a single injection of the DNA-alkylating agent methylazoxymethanol acetate (MAM) during pregnancy, which also causes schizophrenia phenotypes in adult rats, leads to anomalies in PVI and neuronal synchronization (Lodge et al., 2009; Penschuck et al., 2006). MAM-treated rats have also decreased brain GSH levels (Cleland et al., 2013, abstract Neuroscience Meeting).”

• cites Lodge et al., 2009Not checked yet

  Not checked in the free run.

• cites Penschuck et al., 2006Not checked yet

  Not checked in the free run.

• cites Cleland et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

In rats with a neonatal ventral hippocampal lesion, the normal peri-adolescent maturation of parvalbumin interneurons is impaired, and these interneurons show evidence of oxidative stress before behavioral deficits appear.

“In rats with a neonatal ventral hippocampal lesion, the normal peri-adolescent maturation of PVI is impaired (Tseng et al., 2008), and in this model PVI show evidence of oxidative stress prior to the onset of behavioral deficits (O’Donnell et al., 2011).”

• cites Tseng et al., 2008Not checked yet

  Not checked in the free run.

• cites O’Donnell et al., 2011Not checked yet

  Not checked in the free run.

May combine two claims.

Excess oxidative stress also affects perineuronal nets, which can in turn impact parvalbumin interneurons.

“However, excess of oxidative stress also affects PNN (Cabungcal et al., 2013b), which can in turn impact PVI.”

• cites Cabungcal et al., 2013bNot checked yet

  Not checked in the free run.

May combine two claims.

Inhibition of glutathione synthesis restricted to parvalbumin interneurons is sufficient to affect these interneurons, and oxidative stress precedes the parvalbumin interneuron deficit.

“Interestingly, an inhibition of GSH synthesis restricted to PVI is sufficient to affect these interneurons (Cabungcal et al., 2013b) and oxidative stress precedes the PVI deficit (Steullet et al., 2010).”

• cites Cabungcal et al., 2013bNot checked yet

  Not checked in the free run.

• cites Steullet et al., 2010 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Fast-spiking parvalbumin interneurons are energy demanding, requiring optimal mitochondrial performance with enhanced metabolic activity and oxidative phosphorylation, which leads to elevated mitochondria-generated reactive oxygen species.

“To support high-frequency neuronal synchronization, fast-spiking PVI are energy demanding. This requires optimal mitochondrial performance (Kann et al., 2011) with enhanced metabolic activity and oxidative phosphorylation (Harris et al., 2012) leading to elevated mitochondria-generated ROS.”

• cites Kann et al., 2011Not checked yet

  Not checked in the free run.

• cites Harris et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In Gclm knockout mice with chronic glutathione deficit, a dopamine reuptake inhibitor applied during postnatal development permanently decreases the density of parvalbumin-immunoreactive cells in the anterior cingulate cortex, but not when applied in adulthood.

“In mice with a chronic GSH deficit (Gclm KO mice, Kulak et al., 2012), administration of a dopamine re-uptake inhibitor (GBR-12909), which partially mimics dopamine release during psychosocial stress (Lataster et al., 2011) and produces ROS via the catabolism of dopamine (Cadet and Brannock, 1998; Rabinovic and Hastings, 1998), decreases permanently the density of parvalbumin-immunoreactive cells”

• cites Kulak et al., 2012Not checked yet

  Not checked in the free run.

• cites Lataster et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites Cadet and Brannock, 1998Not checked yet

  Not checked in the free run.

May combine two claims.

White matter anomalies are observed in ultra high-risk subjects and first-episode patients, suggesting a neurodevelopmental component for this impairment.

“Although less consistent than in chronic patients, white matter anomalies are observed in ultra high-risk subjects and first-episode patients (Fitzsimmons et al., 2013; Kyriakopoulos and Frangou, 2009), suggesting a neurodevelopmental component for this impairment.”

• cites Fitzsimmons et al., 2013Not checked yet

  Not checked in the free run.

• cites Kyriakopoulos and Frangou, 2009Not checked yet

  Not checked in the free run.

May combine two claims.

Oligodendrocytic and myelination anomalies in schizophrenia could affect axonal integrity and conduction velocity, disrupting temporal control of long-range brain synchronization.

“Oligodendrocytic and myelination anomalies in schizophrenia could affect axonal integrity and conduction velocity (Whitford et al., 2011), with the consequence of disrupting temporal control of long-range brain synchronization.”

• cites Whitford et al., 2011Not checked yet

  Not checked in the free run.

May combine two claims.

Lack of NMDAR-mediated signaling causes a reduction in PGC-1α levels and expression of several antioxidant enzymes, and decreases glutathione levels.

“However, the lack of NMDAR-mediated signaling also causes a reduction in PGC-1α levels and expression of several antioxidant enzymes (Jiang et al., 2013), and decreases GSH levels (Stojkovic et al., 2012).”

• cites Jiang et al., 2013Not checked yet

  Not checked in the free run.

• cites Stojkovic et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Supporting observations for oligodendrocyte impairment in schizophrenia include decreased expression of oligodendrocyte-related genes, impaired oligodendrocyte maturation, reduced number and/or density of oligodendrocytes in gray and white matter, apoptotic oligodendrocytes, and ultrastructural alterations in myelinated fibers.

“The observations supporting this claim include decreased expression of oligodendrocyte-related genes (Hakak et al., 2001; Katsel et al., 2005; Tkachev et al., 2003), impairment of oligodendrocyte maturation (Kerns et al., 2010), reduced number and/or density of oligodendrocytes in gray and white matter (Byne et al., 2008; Hof et al., 2003; Uranova et al., 2004), apoptotic oligodendrocytes and ult”

• cites Hakak et al., 2001 sourceNot checked yet

  Not checked in the free run.

• cites Katsel et al., 2005Not checked yet

  Not checked in the free run.

• cites Tkachev et al., 2003Not checked yet

  Not checked in the free run.

May combine two claims.

This oligodendrocyte deficit recovers in adulthood and is accompanied by an increase in prefrontal N-acetylaspartate, suggesting impaired myelin lipid synthesis during prefrontal cortical maturation.

“This deficit, which recovers in adulthood, is accompanied by an increase in prefrontal N-acetylaspartate (das Neves Duarte et al., 2012), suggesting an impaired myelin lipid synthesis during prefrontal cortical maturation (Kulak et al., 2013).”

• cites das Neves Duarte et al., 2012Not checked yet

  Not checked in the free run.

• cites Kulak et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In these mice, social isolation exacerbates oxidative stress and parvalbumin interneuron deficits, both of which are prevented by a NOX inhibitor.

“In these mice, social isolation exacerbates oxidative stress and PVI deficits, both of which are prevented by a NOX inhibitor (Jiang et al., 2013).”

• cites Jiang et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Activation of NMDARs in oligodendrocytes modulates their metabolism, promotes their differentiation from immature into mature stage, and favors myelination around axons.

“Activation of these receptors in oligodendrocytes modulates their metabolism, promotes their differentiation from immature into mature stage, and favors myelination around axons (Cao and Yao, 2013; Li et al., 2013).”

• cites Cao and Yao, 2013Not checked yet

  Not checked in the free run.

• cites Li et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Postnatal inhibition of NMDARs causes a deficit not only in parvalbumin interneurons but also in myelination.

“Postnatal inhibition of NMDARs causes deficit not only in PVI, but also in myelination (Zhang et al., 2012).”

• cites Zhang et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Downregulation of antioxidant systems by NMDAR blockade may be particularly significant in parvalbumin interneurons of young individuals, because NMDAR-mediated postsynaptic responses are stronger in immature than in mature parvalbumin interneurons.

“The downregulation of antioxidant systems by NMDAR blockade may be particularly significant in PVI of young individuals, since NMDAR-mediated postsynaptic responses are stronger in immature compared to mature PVI (Rotaru et al., 2011; Wang and Gao, 2009, 2010).”

• cites Rotaru et al., 2011Not checked yet

  Not checked in the free run.

• cites Wang and Gao, 2009, 2010Not checked yet

  Not checked in the free run.

May combine two claims.

Functional down-regulation of NMDARs by oxidative conditions can occur via extracellular redox-sensitive sites on NR1 and NR2A subunits or by Ca2+/calmodulin-dependent protein kinase II.

“Functional down-regulation of NMDARs by oxidative conditions can occur via either extracellular redox-sensitive sites located on NR1 and NR2A subunits (Choi et al., 2001; Kohr et al., 1994) or by Ca2+/calmodulin-dependent protein kinase II (Bodhinathan et al., 2010).”

• cites Choi et al., 2001Not checked yet

  Not checked in the free run.

• cites Kohr et al., 1994Not checked yet

  Not checked in the free run.

• cites Bodhinathan et al., 2010Not checked yet

  Not checked in the free run.

May combine two claims.

Interleukin-6 mediates ketamine-induced NOX upregulation and subsequently parvalbumin interneuron deficits.

“Interleukin-6 mediates ketamine-induced NOX upregulation and subsequently PVI deficits (Behrens et al., 2008).”

• cites Behrens et al., 2008Not checked yet

  Not checked in the free run.

May combine two claims.

A transient postnatal glutathione deficit results in NMDAR hypofunction and impairs parvalbumin interneurons.

“A transient postnatal GSH deficit results in NMDAR hypofunction (Steullet et al., 2006) and impairs PVI (Cabungcal et al., 2006).”

• cites Steullet et al., 2006Not checked yet

  Not checked in the free run.

• cites Cabungcal et al., 2006Not checked yet

  Not checked in the free run.

May combine two claims.

NMDAR hypofunction can weaken antioxidant defenses, contributing to redox dysregulation and affecting cell maturation.

“These observations suggest that NMDAR hypofunction can weaken antioxidant defenses, contributing to a redox dysregulation and affecting cell maturation.”

May combine two claims.

Transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 display enhanced prefrontal oxidative stress and show stronger parvalbumin interneuron deficits following a postnatal immune challenge.

“This combination has been demonstrated in transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1), which display enhanced prefrontal oxidative stress (Johnson et al., 2013) and shows stronger PVI deficits following a postnatal immune challenge (Ibi et al., 2010).”

• cites Johnson et al., 2013Not checked yet

  Not checked in the free run.

• cites Ibi et al., 2010Not checked yet

  Not checked in the free run.

May combine two claims.

Genes related to oligodendrocytes and myelination have been associated with schizophrenia, suggesting that white matter anomalies in this disorder could have a direct genetic origin.

“Genes related to oligodendrocytes and myelination have been associated with schizophrenia (Takahashi et al., 2011), suggesting that white matter anomalies in this disorder could have a direct genetic origin.”

• cites Takahashi et al., 2011Not checked yet

  Not checked in the free run.

May combine two claims.

The intracellular redox state controls the proliferation and differentiation of oligodendrocytes, and low glutathione levels affect oligodendrocyte maturation.

“Furthermore, the intracellular redox state controls the proliferation and differentiation of oligodendrocytes (Li et al., 2007; Smith et al., 2000; Do et al., 2012), and low GSH levels affect oligodendrocyte maturation (French et al., 2009).”

• cites Li et al., 2007Not checked yet

  Not checked in the free run.

• cites Smith et al., 2000Not checked yet

  Not checked in the free run.

• cites French et al., 2009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Redox dysregulation can cause oligodendrocytic developmental anomalies and/or delay in gray and white matter, which may eventually contribute to abnormal myelin sheath and axonal integrity.

“Taken together, these findings indicate that a redox dysregulation can cause oligodendrocytic developmental anomalies and/or delay in gray and white matter which may eventually contribute to abnormal myelin sheath and axonal integrity.”

May combine two claims.

Genetic vulnerabilities and environmental insults that affect homeostasis of either the redox, glutamatergic, or neuroimmune system could affect the other systems with amplified negative consequences on parvalbumin interneuron maturation and subsequently on neuronal network synchronization and information processing.

“Genetic vulnerabilities and environmental insults that would affect homeostasis of either redox, or glutamatergic, or neuroimmune system could affect the other systems with amplified negative consequences on PVI maturation and subsequently on neuronal network synchronization and information processing.”

May combine two claims.

In young Gclm KO mice, NAC restores most neurochemical profiles, such as the glutamine/glutamate ratio, which is similarly altered in first-episode schizophrenia.

“Furthermore, in young Gclm KO mice, NAC normalizes most of the neurochemical profiles, including the glutamime/glutamate ratio known to be altered in a similar way in first-episode schizophrenia patients (das Neves Duarte et al., 2012).”

• cites das Neves Duarte et al., 2012Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Because of the complex interplay between redox, immune, and glutamatergic systems, combinations of genetic and environmental risk factors could generate a vicious circle of dysregulation within all these systems, ultimately giving rise to abnormal functional and structural connectivity deficits as observed in schizophrenia.

“Because of the complex interplay between redox, immune, and glutamatergic systems, we propose that combinations of genetic and environmental risk factors could generate a vicious circle of dysregulation within all these systems, ultimately giving rise to abnormal functional and structural connectivity deficits, as observed in schizophrenia.”

• AssumptionThe authors state this as an assumption: The central hub hypothesis, which is based mainly on observations and experiments in rodent models, applies to human schizophrenia.

Probably not a substantial claim: may not pass S3 (load-bearing).

Metabolic signatures of reactivity to oxidative stress in cells derived from patients and controls can potentially be used as biomarkers for early psychosis.

“Metabolomic approach in cells derived from patients and controls highlights the possibility of using metabolic signatures of reactivity to oxidative stress as biomarkers for early psychosis (Fournier et al., 2014).”

• cites Fournier et al., 2014 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Altered stress-reactivity is a vulnerability marker for psychosis.

“Increasing evidence points to altered stress-reactivity as a vulnerability marker for psychosis (Myin-Germeys et al., 2003; Lataster et al., 2013).”

• cites Myin-Germeys et al., 2003 sourceNot checked yet

  Not checked in the free run.

• cites Lataster et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

The data compiled in this review strongly suggest that genetic and environmental risk factors leading to dysregulation of the redox, neuroimmune, and glutamatergic hub would invariably affect parvalbumin interneurons and white matter, and consequently impair long- and short-range neuronal network connectivity.

“The data compiled in the present review strongly suggest that genetic and environmental risk factors, which lead to dysregulation of the “hub” comprised of redox, neuroimmune and glutamatergic systems, would invariably affect PVI and white matter, and consequently impair long- and short-range neuronal network connectivity.”

• AssumptionThe authors state this as an assumption: The central hub hypothesis, which is based mainly on observations and experiments in rodent models, applies to human schizophrenia.

May combine two claims.

Minocycline prevents hypomyelination induced by immune challenge, and its protective effect is associated with decreased microglial activation, cytokine levels, and oxidative stress.

“Finally, the tetracycline antibiotic, minocycline, prevents hypomyelination induced by immune challenge, and its protective effect is associated with decreased microglial activation, cytokine levels, and oxidative stress (Fan et al., 2005).”

• cites Fan et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

NAC boosts the astrocytic cystine/glutamate antiporter, increasing cystine uptake and glutamate release outside cells.

“Finally, NAC upregulates the activity of the astrocytic cystine/glutamate antiporter, leading to cellular entry of cystine (which can be reduced to cysteine and incorporated into GSH) and extracellular release of glutamate (Bridges et al., 2012).”

• cites Bridges et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Some phase III trials of glutamatergic agents were inconclusive, while smaller studies using D-serine at the NMDAR glycine site suggest positive effects.

“Several promising clinical phase III trials aiming to act on the glutamatergic system proved inconclusive, but other relatively small scale clinical studies targeting the glycine site of NMDAR using D-serine indicate positive effects (Kantrowitz and Javitt, 2012).”

• cites Kantrowitz and Javitt, 2012Not checked yet

  Not checked in the free run.

May combine two claims.

The cystine/glutamate antiporter is key for extrasynaptic glutamate levels, which control synaptic glutamate release through presynaptic mGluR2/3.

“This antiporter plays an important role in the regulation of extrasynaptic glutamate levels, which in turn regulate synaptic glutamate release via presynaptic mGluR2/3 (Baker et al., 2002).”

• cites Baker et al., 2002Not checked yet

  Not checked in the free run.

May combine two claims.

Parvalbumin interneurons and oligodendrocytes are affected by similar early-life insults and by disruption of the redox, neuroimmune, and glutamatergic systems.

“Taken together, it is remarkable that PVI and oligodendrocytes are affected by similar early-life insults and by the disruption of redox, neuroimmune and glutamatergic systems.”

May combine two claims.

In Schnurri-2 knockout mice, a genetic model of enhanced pro-inflammation, the expression of myelin-associated proteins is reduced, which could be due to NOX upregulation.

“In a genetic model of enhanced pro-inflammation (Schnurri-2 KO mice), the expression of myelin-associated proteins is reduced, which could be due to a NOX upregulation (Takao et al., 2013).”

• cites Takao et al., 2013Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The mechanism behind psychotic stress reactivity may involve dopamine neurons being hyper-reactive to environmental stimuli and stress.

“The biological mechanism underlying psychotic reactivity to stress could be related to hyper-reactivity of dopamine neurons to environmental stimuli and stress (Lataster et al., 2011; Mizrahi et al., 2012; Myin-Germeys et al., 2005).”

• cites Lataster et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites Mizrahi et al., 2012Not checked yet

  Not checked in the free run.

• cites Myin-Germeys et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

Maternal and early postnatal immune challenges impair myelination and long-range synchronization.

“Maternal and early postnatal immune challenges impair myelination (Fan et al., 2005; Makinodan et al., 2008; Paintlia et al., 2008) and long-range synchronization (Dickerson et al., 2010).”

• cites Fan et al., 2005Not checked yet

  Not checked in the free run.

• cites Makinodan et al., 2008Not checked yet

  Not checked in the free run.

• cites Paintlia et al., 2008Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Other systems, such as the dopamine system, and their reciprocal interactions with the proposed hub certainly participate in schizophrenia pathology.

“Moreover, we have to emphasize that other systems such as the dopamine system known to be implicated in schizophrenia and their reciprocal interactions with the proposed “hub” (see: Avshalumov et al., 2007; Baker et al., 2002; Kulak et al., 2013; Lodge and Grace, 2011; Meiser et al., 2013; Meyer and Feldon, 2009; Moller et al., 2013; Steullet et al., 2008) certainly participate to the pathology.”

• cites Avshalumov et al., 2007Not checked yet

  Not checked in the free run.

• cites Baker et al., 2002Not checked yet

  Not checked in the free run.

• cites Kulak et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The decreased expression of myelin-related genes induced by cytokines Il-1β and TNF-α in human primary oligodendrocytes is blocked by N-acetylcysteine, suggesting that these inflammatory molecules act through redox dysregulation.

“Moreover, the decreased expression of myelin-related genes induced by cytokines (Il-1β and TNF-α) in human primary oligodendrocytes is blocked by NAC (Jana and Pahan, 2005), suggesting that these inflammatory molecules act through redox dysregulation.”

• cites Jana and Pahan, 2005Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

The hypothesis rests largely on rodent observations and experiments and presumes similar mechanisms in humans.

“We have however to acknowledge that this hypothesis is based mostly on observations and experiments in rodent models and postulates that the mechanisms are similar in humans.”

May combine two claims.

NAC is a safe candidate for preventing or treating schizophrenia and other psychiatric disorders.

“Therefore, it represents a safe and potential compound for the prevention or treatment of schizophrenia and other psychiatric disorders (Berk et al., 2013).”

• cites Berk et al., 2013 sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: NAC has anti-inflammatory effects, likely via its antioxidant properties.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

One reason for the shared vulnerability of parvalbumin interneurons and oligodendrocytes could be their high metabolic requirement.

“One reason for this shared vulnerability could be related to the high metabolic requirement of these two cell types.”

May combine two claims.

NAC might lower synaptic glutamate release and indirectly boost NMDAR function through its antioxidant and redox-regulating actions.

“Thus, NAC could be useful to reduce synaptic glutamate release and to indirectly enhance NMDAR function via its antioxidant and redox regulator properties.”

• AssumptionRests on an assumption: NAC is deacetylated to cysteine, the rate-limiting GSH precursor, so it upregulates GSH synthesis when cells have excess ROS.

May combine two claims.

Microglial cells and cytokines participate in normal brain development, so dysregulation of cytokine-mediated pathways could disrupt normal developmental processes.

“As microglial cells and cytokines participate in normal brain development (Bilbo and Schwarz, 2012; Kettenmann et al., 2013), a dysregulation of cytokine-mediated pathways could disrupt normal developmental processes.”

• cites Bilbo and Schwarz, 2012Not checked yet

  Not checked in the free run.

• cites Kettenmann et al., 2013 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

NAC normalized neuronal activity and connectivity.

“In addition, NAC normalized neuronal activity and connectivity and improved mismatch-negativity (Lavoie et al., 2008), an auditory-related, NMDA-dependent evoked potential typically impaired in schizophrenia (Umbricht et al., 2000).”

• cites Lavoie et al., 2008Not checked yet

  Not checked in the free run.

May combine two claims.

NAC's benefit should be viewed cautiously, as current evidence comes from few studies with only moderate improvement in chronic schizophrenia.

“However, the beneficial effect of NAC has to be taken with caution since the current data is based on only a few studies showing relatively moderate clinical improvement in chronic schizophrenia patients, probably due to the low bioavailability and membrane permeability of NAC which enters the brain at a very modest rate (Farr et al., 2003).”

Probably not a substantial claim: may not pass S2 (checkable).

Targeting neuroinflammation, oxidative stress, and NMDAR hypofunction early in development and disease may lessen neuropathology and lower the risk of clinical symptoms.

“In contrast, we propose that targeting neuroinflammation, oxidative stress, and NMDAR hypofunction at critical developmental periods and early in the disease may reduce neuropathological anomalies and alleviate the risk of emergence of clinical manifestations.”

May combine two claims.

Molecules targeting redox, immune, and glutamatergic systems, including NAC, might help at-risk youth more than chronic patients, since PVI and myelin defects may precede illness onset.

“Moreover, NAC or other molecules that target redox, immune, and glutamatergic systems may be more beneficial for young subjects at risk than for chronic patients because the defects in PVI and oligodendrocytes/myelination may precede illness onset.”

May combine two claims.

Brain maturation is genetically controlled and shaped by environmental insults, so different regions may be vulnerable to hub dysregulation at specific developmental times.

“Brain maturation mechanisms are under genetic control and influenced by environmental insults, suggesting that different brain regions could be vulnerable to a dysregulation of the “hub” during specific developmental periods.”

• AssumptionRests on an assumption: Brain development follows ordered events: proliferation, differentiation, migration, formation, and maturation of neuronal circuits.
• AssumptionRests on an assumption: The pace of development varies among brain structures, with the prefrontal cortex being the last to mature.
• AssumptionRests on an assumption: Brain maturation mechanisms are under genetic control and influenced by environmental insults.

Probably not a substantial claim: may not pass S2 (checkable).

The reviewed evidence suggests early intervention during brain development on all three hub elements is worthwhile.

“The body of knowledge reviewed above suggests that it would be worth to intervene early during brain development on all three elements of the proposed “hub”.”

May combine two claims.

Mismatch negativity is an auditory, NMDA-dependent evoked potential that is usually impaired in schizophrenia.

“In addition, NAC normalized neuronal activity and connectivity and improved mismatch-negativity (Lavoie et al., 2008), an auditory-related, NMDA-dependent evoked potential typically impaired in schizophrenia (Umbricht et al., 2000).”

• cites Umbricht et al., 2000Not checked yet

  Not checked in the free run.

May combine two claims.

In an initial randomized, double-blind, placebo-controlled trial, adding NAC for chronic patients reduced negative symptoms and improved global functioning.

“In a first randomized double-blind placebo-controlled trial, an add-on treatment of NAC in chronic patients diminished negative symptoms and improved global functioning (Berk et al., 2008).”

• cites Berk et al., 2008 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Sulforaphane boosts Nrf2-dependent phase II detoxification enzymes and antioxidant proteins, including the cystine/glutamate antiporter and GSH enzymes.

“Finally, it would be also worth investigating compounds such as sulforaphane (Shirai et al., 2012) that up-regulate Nrf2-dependent phase II detoxification enzymes and antioxidant proteins which include the cystine/glutamate antiporter and enzymes of the GSH system (Lavoie et al., 2009).”

• cites Shirai et al., 2012Not checked yet

  Not checked in the free run.

• cites Lavoie et al., 2009Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Genetic vulnerability factors may not lend themselves to therapeutic interventions, although they are important as potential biomarkers for high-risk individuals.

“The genetic vulnerability factors, although important as potential biomarkers for high-risk individuals, may not lend themselves to therapeutic interventions.”