Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic e...Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated.In addition,17β-Estradiol（E2）plays a crucial role in neurodevelopment and induces an increase in synaptic proteins.The post-synaptic density 95（PSD95）protein,which is involved in the development of the structure and function of new spines and localized with estrogen receptor α（ERα）at the post-synaptic density（PSD）,was detected in our study by using hippocampal neuron cell line HT22.We found that LCT up-regulated PSD95 and ERα expression,estrogen receptor（ER）antagonist ICI182,780 and phosphatidylinositol-4;5-bisphosphate 3-kinase（PI3K）inhibitor LY294,002 blocked this effect.In addition,LCT disrupted the promotion effect of E2 on PSD95.To investigate whether the observed changes are caused by ERα-dependent signaling activation,we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B（PKB/Akt）-eukaryotic initiation factor（e IF）4E-binding protein 1（4E-BP1）pathway.There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment.In addition,LCT could disrupt the activation effect of E2 on the Akt pathway.However,no changes in c AMP response element-binding protein（CREB）activation and PSD95 messenger ribonucleic acid（m RNA）were observed.Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway,and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.展开更多
Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS...Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.展开更多
Neuropeptide Y (NPY), a metabolism-related cardiovascular factor, plays a crucial role in blood pressure(BP) regulation via peripheral and central pathways. The expression of NPY receptors (Y1R/Y2R) specific to barore...Neuropeptide Y (NPY), a metabolism-related cardiovascular factor, plays a crucial role in blood pressure(BP) regulation via peripheral and central pathways. The expression of NPY receptors (Y1R/Y2R) specific to baroreflex afferents impacts on the sexually dimorphic neural control of circulation. This study was designed to investigate the expression profiles of NPY receptors in the nodose ganglion (NG) and nucleus tractus solitary (NTS) under hypertensive conditions. To this end, rats with hypertension induced by NG-nitro-L-arginine methylester (L-NAME) or high fructose drinking (HFD), and spontaneously hypertensive rats (SHRs) were used to explore the effects/mechanisms of NPY on BP using functional, molecular, and electrophysiological approaches. The data showed that BP was elevated along with baroreceptor sensitivity dysfunction in model rats;Y1R was up-or down-regulated in the NG or NTS of male and female HFD/L-NAME groups,while Y2R was only down-regulated in the HFD groups as well as in the NG of the male L-NAME group. In SHRs,Y1R and Y2R were both down-regulated in the NTS, and not in the NG. In addition to NPY-mediated energy homeostasis, leptin-melanocortin activation may be essential for metabolic disturbance-related hypertension. We found that leptin and a-melanocyte stimulating hormone (aMSH) receptors were aberrantly down-regulated in HFD rats. In addition, a-MSH concentrations were reduced and NPY concentrations were elevated in the serum and NTS at 60 and 90 min after acute leptin infusion. Electrophysiological recordings showed that the decay time-constant and area under the curve of excitatory post-synaptic currents were decreased by Y1R activation in A-types, whereas, both were increased by Y2R activation in Ah-or C-types. These results demonstrate that sex-and afferent-specific NPY receptor expression in the baroreflex afferent pathway is likely to be a novel target for the clinical management of metabolism-related and essential hypertension.展开更多
Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes t...Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.展开更多
Silicon nanomembrane（SiNM）transistors gated by chitosan membrane were fabricated on plastic substrate to mimic synapse behaviors.The device has both a bottom proton gate（BG）and multiple side gates（SG）.Electrical...Silicon nanomembrane（SiNM）transistors gated by chitosan membrane were fabricated on plastic substrate to mimic synapse behaviors.The device has both a bottom proton gate（BG）and multiple side gates（SG）.Electrical transfer properties of BG show hysteresis curves different from those of typical SiO2 gate dielectric.Synaptic behaviors and functions by linear accumulation and release of protons have been mimicked on this device：excitatory post-synaptic current（EPSC）and paired pulse facilitation behavior of biological synapses were mimicked and the paired-pulse facilitation index could be effectively tuned by the spike interval applied on the BG.Synaptic behaviors and functions,including short-term memory and long-term memory,were also experimentally demonstrated in BG mode.Meanwhile,spiking logic operation and logic modulation were realized in SG mode.展开更多
Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the for...Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.展开更多
基金supported by the National Natural Science Foundation of China(No.H2607-30571585)
文摘Lambda-cyhalothrin（LCT）,one of the type II pyrethroids,has been widely used throughout the world.The estrogenic effect of LCT to increase cell proliferation has been well established.However,whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated.In addition,17β-Estradiol（E2）plays a crucial role in neurodevelopment and induces an increase in synaptic proteins.The post-synaptic density 95（PSD95）protein,which is involved in the development of the structure and function of new spines and localized with estrogen receptor α（ERα）at the post-synaptic density（PSD）,was detected in our study by using hippocampal neuron cell line HT22.We found that LCT up-regulated PSD95 and ERα expression,estrogen receptor（ER）antagonist ICI182,780 and phosphatidylinositol-4;5-bisphosphate 3-kinase（PI3K）inhibitor LY294,002 blocked this effect.In addition,LCT disrupted the promotion effect of E2 on PSD95.To investigate whether the observed changes are caused by ERα-dependent signaling activation,we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B（PKB/Akt）-eukaryotic initiation factor（e IF）4E-binding protein 1（4E-BP1）pathway.There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment.In addition,LCT could disrupt the activation effect of E2 on the Akt pathway.However,no changes in c AMP response element-binding protein（CREB）activation and PSD95 messenger ribonucleic acid（m RNA）were observed.Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway,and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
基金supported by the National Natural Science Foundation of China(No. 30971021,81030023 and 30901550)
文摘Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.
基金grants from the National Natural Science Foundation of China(31171122,81573431,81773731,81971326,and 8190130222).
文摘Neuropeptide Y (NPY), a metabolism-related cardiovascular factor, plays a crucial role in blood pressure(BP) regulation via peripheral and central pathways. The expression of NPY receptors (Y1R/Y2R) specific to baroreflex afferents impacts on the sexually dimorphic neural control of circulation. This study was designed to investigate the expression profiles of NPY receptors in the nodose ganglion (NG) and nucleus tractus solitary (NTS) under hypertensive conditions. To this end, rats with hypertension induced by NG-nitro-L-arginine methylester (L-NAME) or high fructose drinking (HFD), and spontaneously hypertensive rats (SHRs) were used to explore the effects/mechanisms of NPY on BP using functional, molecular, and electrophysiological approaches. The data showed that BP was elevated along with baroreceptor sensitivity dysfunction in model rats;Y1R was up-or down-regulated in the NG or NTS of male and female HFD/L-NAME groups,while Y2R was only down-regulated in the HFD groups as well as in the NG of the male L-NAME group. In SHRs,Y1R and Y2R were both down-regulated in the NTS, and not in the NG. In addition to NPY-mediated energy homeostasis, leptin-melanocortin activation may be essential for metabolic disturbance-related hypertension. We found that leptin and a-melanocyte stimulating hormone (aMSH) receptors were aberrantly down-regulated in HFD rats. In addition, a-MSH concentrations were reduced and NPY concentrations were elevated in the serum and NTS at 60 and 90 min after acute leptin infusion. Electrophysiological recordings showed that the decay time-constant and area under the curve of excitatory post-synaptic currents were decreased by Y1R activation in A-types, whereas, both were increased by Y2R activation in Ah-or C-types. These results demonstrate that sex-and afferent-specific NPY receptor expression in the baroreflex afferent pathway is likely to be a novel target for the clinical management of metabolism-related and essential hypertension.
基金supported in part by National Institutes of Health Grants NS-079331(to MY)and NS-091201(to MY)
文摘Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator（t PA） from the presynaptic terminal of cerebral cortical neurons.Once in the synaptic cleft this t PA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles,and regulates the postsynaptic response to the presynaptic release of glutamate.Indeed,t PA has a bidirectional effect on the composition of the postsynaptic density（PSD） that does not require plasmin generation or the presynaptic release of glutamate,but varies according to the baseline level of neuronal activity.Hence,in inactive neurons t PA induces phosphorylation and accumulation in the PSD of the Ca^（2＋）/calmodulin-dependent protein kinase IIα（pCa MKIIα）,followed by pCa MKIIα-induced phosphorylation and synaptic recruitment of Glu R1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid（AMPA） receptors.In contrast,in active neurons with increased levels of pCa MKIIα in the PSD t PA induces pCa MKIIα and p Glu R1 dephosphorylation and their subsequent removal from the PSD.These effects require active synaptic N-methyl-D-aspartate（NMDA） receptors and cyclin-dependent kinase 5（Cdk5）-induced phosphorylation of the protein phosphatase 1（PP1） at T320.These data indicate that t PA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCa MKIIα/PP1 switch in the PSD.
基金Project supported by the National Natural Science Foundation of China(No.51322201)the Specialized Research Fund for the Doctoral Program of Higher Education(No.20120071110025)Science and Technology Commission of Shanghai Municipality(No.14JC1400200)
文摘Silicon nanomembrane（SiNM）transistors gated by chitosan membrane were fabricated on plastic substrate to mimic synapse behaviors.The device has both a bottom proton gate（BG）and multiple side gates（SG）.Electrical transfer properties of BG show hysteresis curves different from those of typical SiO2 gate dielectric.Synaptic behaviors and functions by linear accumulation and release of protons have been mimicked on this device：excitatory post-synaptic current（EPSC）and paired pulse facilitation behavior of biological synapses were mimicked and the paired-pulse facilitation index could be effectively tuned by the spike interval applied on the BG.Synaptic behaviors and functions,including short-term memory and long-term memory,were also experimentally demonstrated in BG mode.Meanwhile,spiking logic operation and logic modulation were realized in SG mode.
基金The work is funded by Science Foundation Ireland Investigator＇s award （13/IA/1787） and NUI Galway RSU002.
文摘Neurexins （NRXNs） have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.
