ABSTRACT
Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.
Subject(s)
Mice , Animals , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Amyloid beta-Protein Precursor/metabolism , Mice, Transgenic , Neurons/metabolism , Receptors, AMPA/metabolism , Disease Models, AnimalABSTRACT
Objective To establish a postpartum depression animal model induced by pre-pregnancy stress,assess abnormal maternal depressive-like behavior,observe the expression of disrupted-in-schizophrenia 1 (DISC1) in the hippocampus,and detect serum estradiol and corticosterone.Methods A total of 32 female Balb/c were assigned to two groups using random number table:the control group and the pre-pregnancy stressed group(model group),and the model group was subjected to 3 weeks of chronic restraint stress. After the last stressor,the control group and the model group were housed with a male. About 4 weeks later,the mice gave birth to pups. Then at 3 weeks postpartum,open field test,tail suspension test,and sucrose preference test were carried out. The expressions of DISC1 mRNA and protein of hippocampus were detected by real-time quantitative polymerase chain reaction and Western blot,respectively. The serum levels of estradiol and corticosterone were detected with enzyme linked immunosorbent assay. Results After 3 weeks of postpartum,the model mice showed depression-like behaviors. In the open field test,there was no effect on the total distance moved or time spent in the center field (P>0.05). Immobility in tail suspension test was significantly increased (t=-4.950,P<0.001) and sucrose preference was significantly reduced in model group (t=2.475,P<0.05). There was significant statistical difference between control and model group on the expression of DISC1 mRNA (t=-8.915,P<0.001) and protein (t=-5.004,P<0.01) in hippocampus. There was no significant statistical difference on estradiol and corticosterone between two groups (P>0.05). Conclusion Chronic pre-pregnancy stress can induce dams into postpartum depression.The pathogenesis of postpartum depression may be related to the regulation of DISC1 in the hippocampus.
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Objective:To investigate the immune mechanism of Shengxian decoction in experimental autoimmune myasthenia gravis(EAMG) rats. Methods:Lewis rats were immunized with the rat sequence 97-116 of the AChRαsubunit(Rα97-116) in CFA, 25 of which were successful. They were randomly divided into 5 groups:EAMG model group,prednisone group(5. 4 mg/kg),Shengxian decoction low, medium, high dose groups ( dosage 2. 6 g/kg, 5. 2 g/kg, 10. 4 g/kg ) . Clinical symptoms, weight, and the decrement percentage of RNS(5 Hz) were evaluated,and ELISA were adopted to determine the titers of AChR Ab,TGF-β,IFN-γ,IL-2,IL-4 and IL-17 in serum. Results:After molding,the percentage of decrement of RNS in each group noticeably increased by more than 10% in comparison with that in the CFA control group ( P<0. 01 or P<0. 05 ) . At the same time, they were also subjected to progressive decreasing weight and typical myasthenia symptoms,showing the successful molding. With medication,the decrement percentage of RNS of rats in the groups with low,medium and high dose of Shengxian decoction were all on obvious decline with alleviated weight decrease (P<0. 01),testifying to the symptom improvement. Compared with the CFA control group,the groups with low,medium and high dose of Shengxian decoction were coupled with decreasing AChR Ab content(P<0. 05),rising TGF-βlevel and reducing IFN-γ,IL-2,IL-4 and IL-17 level(P<0. 01 or P<0. 05). Conclusion: Shengxian decoction can turn the decrement percentage of RNS around,improve the progressive weight decrease in EAMG rats and increase the weight gains. By up-regulating the TGF-βlevel,lowering IFN-γ,IL-2,IL-4 and IL-17 level,preventing B cells from producing AChR Ab and reducing the content of AChR Ab in serum,it will soothe the damage of NMJ to AChR and cure EAMG.
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Aim To identify whether the petroleum e-ther fraction of Gardenia jasminoides Ellis ( GJ-PE ) could effetive exhibit a rapid antidepressant effect and also to investigate the biological mechanism. Methods Tail suspension test ( TST ) , forced swimming test ( FST ) and novelty suppressed-feeding ( NSF ) were used to screen the rapid antidepressant potential of ef-fective fractions of GJ-PE in KM mice at 24 h post a single administration. Tail suspension test ( TST) was also used at 30 min and forced swimming test ( FST ) was used at 2 h to test the initial onset time of effective fractions of GJ-PE in KM mice. Western blot was per-formed to examine the expression of BDNF and p-eEF2 in hippocampus of KM mice at 2 h and 24 h. Results An acute administration of GJ-PE1 decreased the im-mobility time of KM mice in FST at 2 h and 24 h and decreased the latency time in NSF at 24 h. GJ-PE3 de-creased the latency time in NSF at 24 h. GJ-PE4 in-creased the unit food consumption in NSF at 24 h. At 2 h post a single GJ-PE1 treatment, the expression of BDNF was significantly up-regulated while the expres-sion of p-eEF2 was significantly down-regulated. At 24 h post a single GJ-PE1 treatment, the expression of BDNF was significantly down-regulated while p-eEF2 expression was significantly up-regulated. Conclusion GJ-PE1 has the most significant rapid antidepressant potential among the four fractions of GJ-PE. The effec-tive time of GJ-PE1 is 2 h after drug treatment. The mechanism of the rapid antidepressant effect of GJ-PE1 at 2 h is related to the up-regulation of BDNF and down-regulation of p-eEF2 . GJ-PE3 and GJ-PE4 also have some features of rapid antidepressants. GJ-PE2 doesn′t have the rapid antidepressant potential.
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Aim To observe the rapid antidepressant effect of Yuejuganmaidazao Decoction on postpatum de-pression offspring , and analyze its influence on the Akt and mTOR expression .Methods After postpartum de-pression model was established , the offsprings were randomly divided into the following groups: control group(CTL-F1,n =8), vehicle group (Veh,n =8) and YG group ( YG, n =8 ) .Veh group was treated with vehicle , YG group was treated with Yueju gan-maidazao Decoction(8.3 g· kg -1 ).Forced swimming test(FST) was measured 24 hours after single adminis-tration.The phosphorylation and total level of Akt and m-TOR in the hippocampus was detected by Western blot.Results The immobility time in YG group was significantly shorter than that in Veh group ( P <0.01 ) , and the expression of p-Akt and p-mTOR in the hippocampus was significantly increased ( P <0.05 ) .Conclusion Yuejuganmaidazao Decoction may rapidly alleviate depression-like behaviors of PPD offsprings through upregulation of Akt and mTOR ex-pression .
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Aim Using chronic pre-pregnancy stress to establish a postpartum depression animal model, given a single YG,and acute ketamine was served as control, to explore the pathology of PPD and the anti-depressive mechanism of the YG on the PPD model on AKT/mTOR signaling pathway. Methods Thirty-two fe-male Balb / c were randomly assigned to two groups, the control group ( Control, Con) and the pre-pregnancy stressed group(Model,Mod) , which was subjected to 3 weeks chronic restraint stress. After the last stressor, the pre-pregnancy stressed group was housed with a male. After about 4 weeks later, the mice gave birth to pups. Then at 3 weeks postpartum, we tested the ma-ternal tail suspension test ( TST). Both YG and Ket-amine was single administered 24 hours before behavior test, with single saline for control group and PPD mod-el group. After TST,the mouse hippocampus were ex-tracted to detect the expression of AKT and mTOR. Results After 3 weeks postpartum, the model mice showed depression-like behaviors. Immobility in TST was significantly increased in vehicle groups(P <0. 01). Acute YG improved performance in the TST (P< 0. 01), which was similar to ketamine. And the PPD model mice group showed decreased phosphorylation of AKT and mTOR (P < 0. 01,P < 0. 01), compared to control group. A single dose of YG or ketamine normal-ized AKT/ mTOR signaling in the PPD model mice(P< 0. 01,P < 0. 01),( P < 0. 01,P < 0. 01). Conclu-sions Chronic pre-pregnancy stress can induce dams into postpartum depression and its mechanism maybe associated with down-regulating AKT/ mTOR signa-ling. Acute YG exerts fast antidepressant effect on this PPD model similar to ketamine, and its mechanism may be related to up-regulating AKT/ mTOR signaling in the hippocampus.
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Aim To establish a postpartum depression animal model,assess the abnormal maternal behaviors of depressive dams,and observe the rapid antidepres-sant effects of the Yuejuganmaidazaotang (YG)on the PPD model.Methods Thirty-two female Balb /c were randomly assigned to two groups,the control group (Control,con)and the pre-pregnancy stressed group (Vehicle,veh),and vehicle was subjected to 3 weeks chronic restraint stress.After the last stressor,the pre-pregnancy stressed group was housed with a male.Af-ter about 4 weeks later,the mice gave birth to pups. Then at 3 weeks postpartum,we tested the maternal depressive-like behaviors,including sucrose preference test,forced swimming test and novelty suppressed feeding test.Both YG and Ketamine were single ad-ministered 24 hours before behavior test,with single saline for control group and PPD model group.Results After 3 weeks postpartum,the vehicle mice showed depression-like behaviors.Reduced preference in drinking sucrose solution was found in SPT (P <0.01 ).Immobility in FST was significantly increased in vehicle groups (P <0.01 ).In NSFT,the vehicle group displayed a significantly increased latency and reduced unit of food intake compared with control group(P <0.01,P <0.01 ).Acute YG improved per-formance in the SPT(P <0.01),FST (P <0.01)and NSF (P <0.01,P <0.01),which was similar to ket-amine.Conclusions Chronic pre-pregnancy stress can induce dams into postpartum depression.Acute YG exert fast antidepressant effect on this PPD model simi-lar to ketamine.