N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first ima...N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.展开更多
Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related ps...Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes.However,its precise role and mechanism of action in stress susceptibility remain elusive.In this study,we found a significant reduction in GADD45B expression specifically in the ventral,but not the dorsal hippocampal CA1(dCA1)of stress-susceptible mice.Furthermore,we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation(LTP)in the ventral hippocampal CA1(vCA1).Importantly,through pharmacological inhibition using the NMDA receptor antagonist MK801,we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP.Collectively,these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.展开更多
N-methyl-D-aspartate receptor(NMDAR)trafficking is a key process in the regulation of synaptic efficacy and brain function.However,the molecular mechanism underlying the surface transport of NMDARs is largely unknown....N-methyl-D-aspartate receptor(NMDAR)trafficking is a key process in the regulation of synaptic efficacy and brain function.However,the molecular mechanism underlying the surface transport of NMDARs is largely unknown.Here we identified myosin Va(MyoVa)as the specific motor protein that traffics NMDARs in hippocampal neurons.We found that MyoVa associates with NMDARs through its cargo binding domain.This association was increased during NMDAR surface transport.Knockdown of MyoVa suppressed NMDAR transport.We further demonstrated that Ca^(2+)/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)regulates NMDAR transport through its direct interaction with MyoVa.Furthermore,MyoVa employed Rab11 family-interacting protein 3(Rab11/FIP3)as the adaptor proteins to couple themselves with NMDARs during their transport.Accordingly,the knockdown of FIP3 impairs hippocampal memory.Together,we conclude that in hippocampal neurons,MyoVa conducts active transport of NMDARs in a CaMKII-dependent manner.展开更多
目前治疗药物成瘾的难题主要在于戒毒者的复吸率居高不下。成瘾性药物会给使用者带来极强的欣快感,促进对药物的寻求。形成药物依赖后一旦停止用药,将会出现强烈的负性情绪和不适的躯体反应等戒断症状,场景诱发戒毒者戒断记忆重现是产...目前治疗药物成瘾的难题主要在于戒毒者的复吸率居高不下。成瘾性药物会给使用者带来极强的欣快感,促进对药物的寻求。形成药物依赖后一旦停止用药,将会出现强烈的负性情绪和不适的躯体反应等戒断症状,场景诱发戒毒者戒断记忆重现是产生复吸的首要原因。我们前期研究表明场景提取吗啡戒断记忆时前边缘皮层(prelimbic cortex,PrL)投射到丘脑室旁核(paraventricular nucleus of the thalamus,PVT)神经元(PrL^(-PVT))的c-Fos表达升高,但是PrL^(-PVT)投射神经元是否参与戒断记忆提取以及其分子机制仍然未知。本研究使用条件位置厌恶(conditioned place aversion,CPA)模型结合在体钙信号记录、化学遗传学以及核团定点给药的方法研究了PrL^(-PVT)投射神经元在场景提取吗啡戒断记忆中的作用及分子机制。结果发现:戒断相关场景引起PrL^(-PVT)投射神经元钙信号显著增强;抑制PrL^(-PVT)投射神经元影响戒断记忆提取;激活PrL^(-PVT)投射神经元导致动物逃避相应场景;抑制PrL脑区NMDA受体后,戒断相关场景无法增强PrL^(-PVT)投射神经元的c-Fos及Arc蛋白表达。以上结果表明,PrL^(-PVT)投射神经元的NMDA受体参与场景提取吗啡戒断记忆。本研究对深入认识戒断记忆提取的神经环路机制及干预和防治药物复吸具有重要意义。展开更多
目的观察恩氟烷、异氟烷的遗忘作用与NMDA受体的关系。方法小鼠分别腹腔注射恩氟烷(0.4ml.kg-1)或异氟烷(0.3ml.kg-1)建立遗忘模型,在跳台实验和避暗实验中分别观察不同剂量NMDA(25、50、75ng)侧脑室注射(intracerebroventricular injec...目的观察恩氟烷、异氟烷的遗忘作用与NMDA受体的关系。方法小鼠分别腹腔注射恩氟烷(0.4ml.kg-1)或异氟烷(0.3ml.kg-1)建立遗忘模型,在跳台实验和避暗实验中分别观察不同剂量NMDA(25、50、75ng)侧脑室注射(intracerebroventricular injection,icv)对遗忘小鼠错误次数(error times,ETs)、跳台潜伏期(step down latency,SDL)、步入潜伏期(step through latency,STL)的影响。结果侧脑室注射NMDA(50、75ng)可减少恩氟烷、异氟烷所致遗忘小鼠的ETs,延长SDL和STL。结论侧脑室注射NMDA可部分改善恩氟烷、异氟烷的遗忘作用,NMDA受体是二者所致遗忘作用的重要靶位。展开更多
文摘N-methyl-D-aspartate receptors(NMDARs)play crucial roles in neuronal plasticity and brain function by sensing key neurotransmitters,such as glutamate and glycine.In a tour-de-force,Zhang et al.[1]provide the first images of native NMDARs directly extracted from rat brains,revealing key aspects of NMDAR assembly and diversity.
基金supported by the National Natural Science Foundation of China(82201667,82371195,and 82304474)the Research Fund of Jianghan University(2023JCYJ15).
文摘Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes.However,its precise role and mechanism of action in stress susceptibility remain elusive.In this study,we found a significant reduction in GADD45B expression specifically in the ventral,but not the dorsal hippocampal CA1(dCA1)of stress-susceptible mice.Furthermore,we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation(LTP)in the ventral hippocampal CA1(vCA1).Importantly,through pharmacological inhibition using the NMDA receptor antagonist MK801,we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP.Collectively,these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
基金supported by Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01)Shanghai Center for Brain Science and Brain-Inspired Technology。
基金supported by grants from the STI2030-Major Projects(2021ZD0203502)the National Natural Science Foundation of China(31730107,31970959,and 31671056).
文摘N-methyl-D-aspartate receptor(NMDAR)trafficking is a key process in the regulation of synaptic efficacy and brain function.However,the molecular mechanism underlying the surface transport of NMDARs is largely unknown.Here we identified myosin Va(MyoVa)as the specific motor protein that traffics NMDARs in hippocampal neurons.We found that MyoVa associates with NMDARs through its cargo binding domain.This association was increased during NMDAR surface transport.Knockdown of MyoVa suppressed NMDAR transport.We further demonstrated that Ca^(2+)/calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)regulates NMDAR transport through its direct interaction with MyoVa.Furthermore,MyoVa employed Rab11 family-interacting protein 3(Rab11/FIP3)as the adaptor proteins to couple themselves with NMDARs during their transport.Accordingly,the knockdown of FIP3 impairs hippocampal memory.Together,we conclude that in hippocampal neurons,MyoVa conducts active transport of NMDARs in a CaMKII-dependent manner.
基金supported by the National Natural Science Foundation of China(No.32030051,82271532,31970956,32171025)Fundamental Research Program Funding of Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine(No.JYZZ175).
文摘目前治疗药物成瘾的难题主要在于戒毒者的复吸率居高不下。成瘾性药物会给使用者带来极强的欣快感,促进对药物的寻求。形成药物依赖后一旦停止用药,将会出现强烈的负性情绪和不适的躯体反应等戒断症状,场景诱发戒毒者戒断记忆重现是产生复吸的首要原因。我们前期研究表明场景提取吗啡戒断记忆时前边缘皮层(prelimbic cortex,PrL)投射到丘脑室旁核(paraventricular nucleus of the thalamus,PVT)神经元(PrL^(-PVT))的c-Fos表达升高,但是PrL^(-PVT)投射神经元是否参与戒断记忆提取以及其分子机制仍然未知。本研究使用条件位置厌恶(conditioned place aversion,CPA)模型结合在体钙信号记录、化学遗传学以及核团定点给药的方法研究了PrL^(-PVT)投射神经元在场景提取吗啡戒断记忆中的作用及分子机制。结果发现:戒断相关场景引起PrL^(-PVT)投射神经元钙信号显著增强;抑制PrL^(-PVT)投射神经元影响戒断记忆提取;激活PrL^(-PVT)投射神经元导致动物逃避相应场景;抑制PrL脑区NMDA受体后,戒断相关场景无法增强PrL^(-PVT)投射神经元的c-Fos及Arc蛋白表达。以上结果表明,PrL^(-PVT)投射神经元的NMDA受体参与场景提取吗啡戒断记忆。本研究对深入认识戒断记忆提取的神经环路机制及干预和防治药物复吸具有重要意义。
文摘目的观察恩氟烷、异氟烷的遗忘作用与NMDA受体的关系。方法小鼠分别腹腔注射恩氟烷(0.4ml.kg-1)或异氟烷(0.3ml.kg-1)建立遗忘模型,在跳台实验和避暗实验中分别观察不同剂量NMDA(25、50、75ng)侧脑室注射(intracerebroventricular injection,icv)对遗忘小鼠错误次数(error times,ETs)、跳台潜伏期(step down latency,SDL)、步入潜伏期(step through latency,STL)的影响。结果侧脑室注射NMDA(50、75ng)可减少恩氟烷、异氟烷所致遗忘小鼠的ETs,延长SDL和STL。结论侧脑室注射NMDA可部分改善恩氟烷、异氟烷的遗忘作用,NMDA受体是二者所致遗忘作用的重要靶位。
