Autophagy promotes membrane trafficking of NR2B to alleviate depression by inhibiting AQP4 expression in mice.

Depression is a high-incidence mental illness that seriously affects human health. AQP4 has been reported to be closely associated with depression, while the underlying mechanism is still unclear. This work aimed to investigate the functional role of AQP4 in depression. Depression mouse model was constructed by administration of chronic social defeat stress (CSDS). We found that AQP4 was highly expressed in the hippocampal tissues of CSDS mice. AQP4 knockdown alleviated depression and enhanced the expression of NR2B and PSD95 in CSDS mice. Moreover, primary hippocampal neurons were treated with N-methyl-d-aspartate (NMDA) to induce neuron injury. AQP4 overexpression repressed cell viability and promoted apoptosis of NMDA-treated primary hippocampal neurons. AQP4 up-regulation repressed the expression of NR2B (surface), and enhanced the expression of NR2B (intracellular), P-NR2B, CaMK II and CK2 in the NMDA-treated primary hippocampal neurons. The influence conferred by AQP4 up-regulation was abolished by KN-93 (CaMK II inhibitor) or TBB (CK2 inhibitor) treatment. Rapamycin treatment enhanced the expression of NR2B (surface), and repressed the expression of AQP4, NR2B (intracellular) and P-NR2B in the primary hippocampal neurons by activating autophagy. The activated autophagy alleviated depression in CSDS mice by repressing AQP4 expression. In conclusion, our data demonstrated that autophagy ameliorated depression by repressing AQP4 expression in mice, and AQP4 knockdown promoted membrane trafficking of NR2B and inhibited phosphorylation of NR2B via CaMK II/CK2 pathway. Thus, our work suggests that AQP4 may be a promising molecular target for the development of antidepressant drugs.

Flavonoid fisetin reverses impaired hippocampal synaptic plasticity and cognitive function by regulating the function of AMPARs in a male rat model of schizophrenia.

Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long-term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of this study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N-methyl-D-aspartate receptors (NMDARs) with dizocilpine (MK-801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and cognition-related proteins was measured by western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus-dependent spatial and contextual fear memory in MK-801 rats. In parallel with these behavioral results, fisetin treatment in MK-801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK-801-treated rats. Moreover, fisetin restored the phosphorylation levels of calcium-calmodulin-dependent kinaseII (CaMKII), cAMP response element-binding protein (CREB), and the extracellular signal-regulated kinase (ERK1/2) in MK-801-treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia-associated cognitive deficits.

Long non-coding RNA uc.80- overexpression promotes M2 polarization of microglias to ameliorate depression in rats.

Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non-coding RNA uc.80- is down-regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80- in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80- was down-regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80- overexpression alleviated depression of rats. In addition, uc.80- overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80- overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80- overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80- may be a target gene for depression treatment.

[Improved effects of saponins from Panax japonicus on decline of cognitive function in natural aging rats via NLRP3 inflammasome pathway].

The aim of this paper was to investigate the effect of total saponins from Panax japonicus( SPJ) on cognitive decline of natural aging rats and its mechanism. Thirty male SD rats of eighteen month old were randomly divided into three groups: aged group,10 mg·kg~(-1) SPJ-treated group and 30 mg·kg~(-1) SPJ-treated group. The SPJ-treated groups were given SPJ at the dosages of 10 mg·kg~(-1) and 30 mg·kg~(-1),respectively,from the age of 18 to 24 months. Aged group were lavaged the same amount of saline,10 six-month-old rats were used as control group,with 10 rats in each group. The open field test,novel object recognition and Morris water maze were performed to detect the changes of cognitive function in each group. The changes of synaptic transmission of long-term potentiation( LTP) in hippocampal CA1 region were detected by field potential recording. Western blot was used to detect the protein levels of NLRP3,ASC,caspase-1 and the changes of Glu A1,Glu A2,CAMKⅡ,CREB and phosphorylation of CAMKⅡ,CREB in each group.The results showed that SPJ could improve the decline of cognitive function in aging rats,reduce the damage of LTP in the hippocampal CA1 region of aged rats,and decrease the expression of NLRP3,ASC,caspase-1 in aging rats. At the same time,SPJ could enhance the membrane expression of AMPA receptor( Glu A1 and Glu A2),and increase the expression of p-CAMKⅡand p-CREB in aging rats.SPJ could improve cognitive decline of natural aging rats,and its mechanism may be related to regulating NLRP3 inflammasome,thus regulating the membrane expression of AMPA receptor,and enhancing the expression phosphorylation of CAMKⅡ and CREB.

Sinomenine exerts anticonvulsant profile and neuroprotective activity in pentylenetetrazole kindled rats: involvement of inhibition of NLRP1 inflammasome.

BACKGROUND: Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy. METHODS: The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1ß, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner. CONCLUSIONS: SN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.

Characteristics of the water-soluble components of aerosol particles in Hefei, China.

Size-classified daily aerosol mass concentrations and concentrations of water-soluble inorganic ions were measured in Hefei, China, in four representative months between September 2012 and August 2013. An annual average mass concentration of 169.09 µg/m(3) for total suspended particulate (TSP) was measured using an Andersen Mark-II cascade impactor. The seasonal average mass concentration was highest in winter (234.73 µg/m(3)) and lowest in summer (91.71 µg/m(3)). Water-soluble ions accounted for 59.49%, 32.90%, 48.62% and 37.08% of the aerosol mass concentration in winter, spring, summer, and fall, respectively, which indicated that ionic species were the primary constituents of the atmospheric aerosols. The four most abundant ions were NO3(-), SO4(2-), Ca(2+) and NH4(+). With the exception of Ca(2+), the mass concentrations of water-soluble ions were in an intermediate range compared with the levels for other Chinese cities. Sulfate, nitrate, and ammonium were the dominant fine-particle species, which were bimodally distributed in spring, summer and fall; however, the size distribution became unimodal in winter, with a peak at 1.1-2.1 µm. The Ca(2+) peak occurred at approximately 4.7-5.8 µm in all seasons. The cation to anion ratio was close to 1.4, which suggested that the aerosol particles were alkalescent in Hefei. The average NO3(-)/SO4(2-) mass ratio was 1.10 in Hefei, which indicated that mobile source emissions were predominant. Significant positive correlation coefficients between the concentrations of NH4(+) and SO4(2-), NH4(+) and NO3(-), SO4(2-) and NO3(-), and Mg(2+) and Ca(2+) were also indicated, suggesting that aerosol particles may be present as (NH4)2SO4, NH4HSO4, and NH4NO3.

Interactions between N-ethylmaleimide-sensitive factor and GluR2 in the nucleus accumbens contribute to the expression of locomotor sensitization to cocaine.

Many studies have reported a withdrawal-dependent increase in synaptic AMPA receptor (AMPAR) levels in the nucleus accumbens (NAc) of cocaine-sensitized rats; however, the exact relationship between the expression of sensitization and altered AMPAR surface expression in the NAc has not yet been investigated. We demonstrated that the expression of behavioral sensitization was negatively controlled by N-ethylmaleimide-sensitive factor (NSF)-GluR2 interactions in the NAc. The upregulation of NSF-GluR2 interactions, which may be resulted by the increase in NSF S-nitrosylation after withdrawal from cocaine, was associated with the changes in the expression of behavioral sensitization. Disruption of NSF-GluR2 interactions in the NAc with a specific peptide, TAT-pep-R845A, increased the locomotor response of rats to cocaine by decreasing GluR2 surface insertion. In contrast, prevention of GluR2-containing AMPARs removal from synapses with Pep2-EVKI attenuated the expression of behavioral sensitization. Similarly, treatment with the nitric oxide donor, S-Nitroso-N-acetyl-DL-penicillamine (SNAP), attenuated the expression of locomotor sensitization by promoting GluR2 surface expression. This effect was mediated by the binding of S-nitrosylated NSF to GluR2, which promoted the surface expression of AMPARs. Noticeably, exogenous injection of SNAP into NAc also attenuated the expression of cocaine-induced conditioned place preference. Thus, these results indicate that increased NSF-GluR2 interactions in the NAc after withdrawal from cocaine attenuated the expression of behavioral sensitization and serves as a negative regulatory mechanism in drug-exposed individuals.

Regulation of emotional memory by hydrogen sulfide: role of GluN2B-containing NMDA receptor in the amygdala.

As an endogenous gaseous molecule, hydrogen sulfide (H2 S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2 S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2 S could regulate emotional memory. It was shown that the H2 S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2 S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2 S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2 S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2 S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2 S-associated signaling may hold potential as a new target for the treatment of emotional disorders. In our study, the effect of hydrogen sulfide (H2 S) on amygdala-mediated emotional memory was investigated. It was found that H2 S could enhance amygdala-dependent emotional memory and long-term potentiation (LTP) in rats by selectively increasing the function of GluN2B-containing NMDA receptors in the amygdala. These results suggest that H2 S-associated signaling may be a new target for the treatment of emotional disorders.

Thermal cycling life prediction of Sn-3.0Ag-0.5Cu solder joint using type-I censored data.

Because solder joint interconnections are the weaknesses of microelectronic packaging, their reliability has great influence on the reliability of the entire packaging structure. Based on an accelerated life test the reliability assessment and life prediction of lead-free solder joints using Weibull distribution are investigated. The type-I interval censored lifetime data were collected from a thermal cycling test, which was implemented on microelectronic packaging with lead-free ball grid array (BGA) and fine-pitch ball grid array (FBGA) interconnection structures. The number of cycles to failure of lead-free solder joints is predicted by using a modified Engelmaier fatigue life model and a type-I censored data processing method. Then, the Pan model is employed to calculate the acceleration factor of this test. A comparison of life predictions between the proposed method and the ones calculated directly by Matlab and Minitab is conducted to demonstrate the practicability and effectiveness of the proposed method. At last, failure analysis and microstructure evolution of lead-free solders are carried out to provide useful guidance for the regular maintenance, replacement of substructure, and subsequent processing of electronic products.

Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

Objective: Accumulating evidence has indicated that neurodevelopmental defects may underlie the pathophysiology of bipolar disorder (BD). Insulin-like growth factors (IGFs) are a family of neurotrophic factors that are essential for the survival and development of neurons. The present study aims to investigate whether IGF-2 signaling is implicated in the pathophysiological processes of BD. Method: 50 healthy controls and 78 patients with BD, including 23 patients who diagnosed acute depressive episode and 55 patients who diagnosed acute manic episode, were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) were used to assess the severity of the depressive and manic symptoms, respectively. The serum IGF-2 level was determined by an enzyme-linked immunosorbent assay (ELISA). The Kolmogorov-Smirnov and Mann-Whitney U tests were used for between-group comparisons and spearman analysis was used to analyze correlations. Results: Patients with BD had lower serum IGF-2 levels (66.08 ± 21.22 ng/ml) when compared to healthy controls (88.72 ± 31.55 ng/ml). BD patients were divided into manic episode and depressive episode subgroups. We found that serum IGF-2 levels were reduced in both the mania and depression subgroups (mania: 67.19 ± 21.52 ng/ml, depression: 63.43 ± 20.67 ng/ml; P < 0.001), while no significant difference was observed between two groups (P > 0.05). Spearman correlation analyses revealed that the levels of serum IGF-2 were negatively correlated with the YMRS scores in BD patients (r = -0.522, P < 0.001). Furthermore, IGF-2 was found to be an independent contributor to the severity of symptoms in patients with manic episodes (B = -0.610, t = -5.299, P < 0.001). Conclusion: Lower serum IGF-2 levels were found in BD patients and correlated with the severity of the manic symptoms in these patients during manic episodes. These results suggest that reduced IGF-2 levels might be involved in the pathophysiology of BD, and serum IGF-2 could be a peripheral biomarker for the evaluation of the severity of manic symptoms in BD patients.

Corrigendum: Lower serum insulin-like growth factor 2 level in patients with bipolar disorder is associated with the severity of manic symptoms during manic episodes.

[This corrects the article DOI: 10.3389/fpsyt.2024.1354999.].

Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca²âº-dependent mechanism involving voltage-gated L-type calcium channel.

Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca²âº involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor-phospholipase C-protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A's orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A-induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-ß-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca²âº-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.

Life extension factor klotho regulates behavioral responses to stress via modulation of GluN2B function in the nucleus accumbens.

Klotho is a life extension factor that has the ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here, we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, in which mice are categorized as either susceptible or unsusceptible based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice compared to control or unsusceptible mice. Genetic knockdown of klotho in the NAc induced behavioral alterations relevant to depression in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the behavioral responses to stress in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases in total and synaptic GluN2B expression that were identical to those in susceptible mice. Elevation of klotho in the NAc reversed the reductions in GluN2B expressions and altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates behavioral responses to stress by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, providing new insights into the molecular basis of major depression.

Decreased Plasma Hydrogen Sulfide Level Is Associated With the Severity of Depression in Patients With Depressive Disorder.

Accumulating evidence has suggested a dysfunction of synaptic plasticity in the pathophysiology of depression. Hydrogen sulfide (H2S), an endogenous gasotransmitter that regulates synaptic plasticity, has been demonstrated to contribute to depressive-like behaviors in rodents. The current study investigated the relationship between plasma H2S levels and the depressive symptoms in patients with depression. Forty-seven depressed patients and 51 healthy individuals were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was used to evaluate depressive symptoms for all subjects and the reversed-phase high-performance liquid chromatography (RP-HPLC) was used to measure plasmaH2S levels. We found that plasma H2S levels were significantly lower in patients with depression relative to healthy individuals (P < 0.001). Compared with healthy controls (1.02 ± 0.34 µmol/L), the plasma H2S level significantly decreased in patients with mild depression (0.84 ± 0.28 µmol/L), with moderate depression (0.62 ± 0.21µmol/L), and with severe depression (0.38 ± 0.18 µmol/L). Correlation analysis revealed that plasma H2S levels were significantly negatively correlated with the HAMD-17 scores in patients (r = -0.484, P = 0.001). Multivariate linear regression analysis showed that plasma H2S was an independent contributor to the HAMD-17 score in patients (B = -0.360, t = -2.550, P = 0.015). Collectively, these results suggest that decreased H2S is involved in the pathophysiology of depression, and plasma H2S might be a potential indicator for depression severity.

Erratum to: Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics.

The article "Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics", written by Xue-lin CHAO, Shu-zhen JIANG, Jian-wen XIONG, Jin-qiong ZHAN, Bo WEI, Chun-nuan CHEN, Yuan-jian YANG was originally published electronically on the publisher's internet portal on June 2020 without open access. With the author(s)' decision to opt for Open Choice, the copyright of the article is changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

The association between serum insulin-like growth factor 1 and cognitive impairments in patients with schizophrenia.

Accumulating evidence has shown that insulin-like growth factors (IGFs) are implicated in schizophrenia. Altered serum levels of IGF-1 have been found in schizophrenia patients and are associated with psychopathological symptoms. However, whether there is a relationship between IGF-1 and cognitive impairment in schizophrenia remains unknown. Thirty schizophrenia patients and 26 healthy controls were recruited for this study. The Positive and Negative Syndrome Scale was adopted to assess schizophrenic symptoms, and a battery of neuropsychological tests was employed to evaluate cognitive function. Serum IGF-1 content was determined by enzyme-linked immunosorbent assay (ELISA). We found that patients with schizophrenia performed more poorly than healthy controls in most cognitive tasks, excluding visual memory. The serum IGF-1 concentrations in schizophrenia patients were much lower than those in controls. Correlation analyses revealed that the levels of serum IGF-1 were positively correlated with executive function and attention scores in patients. Furthermore, IGF-1 was an independent contributor to deficits in executive function and attention among schizophrenia patients. Collectively, serum IGF-1 levels were significantly correlated with cognitive performance in schizophrenia patients, indicating that decreased IGF-1 levels might contribute to the pathophysiology of schizophrenia-associated cognitive impairments. The regulation of IGF-1 signaling might be a potential treatment strategy for cognitive impairments in schizophrenia.

Increased Plasma Level of Longevity Protein Klotho as a Potential Indicator of Cognitive Function Preservation in Patients With Schizophrenia.

Cognitive impairments are a core feature of schizophrenia. Klotho is an anti-aging protein with demonstrated cognitive-enhancing effects on the brain. The purpose of this study was to investigate the differences in levels of plasma klotho between patients with schizophrenia and healthy controls, as well as the relationship between klotho level and cognitive function in patients. Forty patients with schizophrenia and 40 gender- and age-matched healthy individuals were recruited. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychopathology of patients. A neuropsychological battery was performed to evaluate the cognitive function of participants. Plasma klotho was measured using enzyme-linked immunosorbent assay. We show that patients with schizophrenia performed worse in the neurocognitive tests than the healthy controls. The levels of plasma klotho were significantly higher in schizophrenia patients than in healthy controls (p < 0.001). In patients, plasma klotho levels were positively correlated with cognitive function with regard to attention (p = 0.010), working memory (p < 0.001), verbal memory (p = 0.044), executive function (p < 0.001), and composite cognitive score (p < 0.001). Stepwise linear regression analysis shows that executive function had the highest correlation with plasma klotho levels (ß = 0.896, t = 8.290, p < 0.001). Collectively, these results indicate that anti-aging protein klotho may be implicated in the pathogenesis of schizophrenia, and increased klotho may act as a compensatory factor for the preservation of cognitive function in schizophrenia. Further studies are needed to investigate the dynamic changes of klotho and the mechanisms by which klotho modulates cognition in schizophrenia.

Changes of Serum Insulin-like Growth Factor-2 Response to Negative Symptom Improvements in Schizophrenia Patients Treated with Atypical Antipsychotics.

Accumulating evidence suggests that a disruption of early brain development, in which insulin-like growth factor-2 (IGF-2) has a crucial role, may underlie the pathophysiology of schizophrenia. Our previous study has shown that decreased serum IGF-2 was correlated with the severity of psychopathology in patients with schizophrenia. Here we conducted a prospective observation trial to investigate the effects of atypical antipsychotics on serum IGF-2 level and its relationship with clinical improvements in schizophrenia patients. Thirty-one schizophrenia patients with acute exacerbation and 30 healthy individuals were recruited in this study. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and serum IGF-2 levels were determined using ELISA. We found that schizophrenia patients with acute exacerbation had lower serum IGF-2 levels than control individuals at baseline (P<0.05). After 2 months of atypical antipsychotic treatment, a significant improvement in each PANSS subscore and total score was observed in patients (all P<0.01), and the serum IGF-2 levels of patients were significantly increased compared with those at baseline (203.13±64.62 vs. 426.99±124.26 ng/mL; t =-5.044, P<0.001). Correlation analysis revealed that the changes of serum IGF-2 levels in patients were significantly correlated with the improvements of negative symptoms (r=-0.522, P=0.006). Collectively, our findings demonstrated changes of serum IGF-2 response to improvements of negative symptoms in schizophrenia patients treated with atypical antipsychotics, suggesting that serum IGF-2 might be a treatment biomarker for schizophrenia.

Decreased Plasma Levels of Growth Differentiation Factor 11 in Patients With Schizophrenia: Correlation With Psychopathology and Cognition.

Schizophrenia is linked with abnormal neurodevelopment, on which growth differentiation factor 11 (GDF-11) has a great impact. However, a direct evidence linking GDF-11 to the pathophysiology of schizophrenia is still lacking. The current study aimed to investigate the relationship between plasma GDF-11 levels and both psychopathological symptoms and cognitive function in schizophrenia. Eighty-seven schizophrenia patients and 76 healthy controls were enrolled in the present study. The symptomatology of schizophrenia was evaluated using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) including twelve neurocognitive tests in five aspects of cognitive function. Plasma GDF-11 levels were determined by enzyme-linked immunosorbent assay (ELISA). We found that plasma levels of GDF-11 were significantly lower in schizophrenia patients relative to healthy controls. Correlation analysis showed significant negative correlations between the GDF-11 levels and the PANSS total score, the positive symptoms score, the negative symptoms score or the general score. Additionally, positive associations were observed between plasma GDF-11 levels and the visuospatial/constructional, attention, immediate memory, or delayed memory in patients. Partial correlation analysis showed that these correlations were still significant after adjusting for age, gender, education years, body mass index, duration of illness, and age of onset except for the visuospatial/constructional and attention index. Multiple regression analysis revealed that GDF-11 was an independent contributor to the immediate memory, delayed memory and RBANS total score in patients. Collectively, the correlations between plasma GDF-11 and psychopathological and cognitive symptoms suggest that abnormal GDF-11 signaling might contribute to schizophrenic psychopathology and cognitive impairments and GDF-11 could be a potential and promising biomarker for schizophrenia.

Altered insulin-like growth factor-2 signaling is associated with psychopathology and cognitive deficits in patients with schizophrenia.

BACKGROUND: Schizophrenia is linked with abnormal brain neurodevelopment, on which IGF-2 (insulin-like growth factor-2) has a great impact. The purpose of this study was to assess the levels of serum IGF-2 and its binding proteins IGFBP-3 and IGFBP-7 in schizophrenia patients and the associations of these proteins with schizophrenia psychopathology and cognitive deficits. METHODS: Thirty-two schizophrenia patients and 30 healthy controls were recruited. The PANSS and a neurocognitive test battery were used to assess schizophrenic symptomatology and cognition, respectively. Serum IGF-2, IGFBP-3 and IGFBP-7 levels were determined using ELISA. RESULTS: The schizophrenia patients had a much lower content of serum IGF-2, IGFBP-3 and IGFBP-7 than controls. For the patients, IGF-2 levels were negatively correlated with the PANSS negative scores and positively associated with working memory, attention, and executive function. The correlations between IGF-2 and the PANSS negative scores, working memory or executive function were still significant after controlling for age, sex, education level, BMI, illness history and age of onset. No significant associations of IGFBP-3 or IGFBP-7 with the PANSS scores and cognitive function were observed in the patients. CONCLUSIONS: Our study demonstrates that serum IGF-2 was significantly correlated with negative and cognitive symptoms in patients with schizophrenia, suggesting that altered IGF-2 signaling may be implicated in the psychopathology and cognitive deficits in schizophrenia.