During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membra...During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.展开更多
Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt)...Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.展开更多
Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether t...Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether these neurons indeed form physiologically functional autapses.We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release(AR)of neurotransmitters after bursts of high-frequency action potentials(APs).Surprisingly,we found no autaptic AR in SPNs,even in the presence of Sr^(2+).However,robust autaptic AR was recorded in parvalbumin(PV)-expressing neurons.The autaptic responses were mediated by GABA_(A) receptors and their strength was dependent on AP frequency and number.Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations.Together,our results indicate that PV neurons,but not SPNs,form functional autapses,which may play important roles in striatal functions.展开更多
Medium spiny neurons(MSNs)in the striatum,which can be divided into D1 and D2 MSNs,originate from the lateral ganglionic eminence(LGE).Previously,we reported that Six3 is a downstream target of Sp8/Sp9 in the transcri...Medium spiny neurons(MSNs)in the striatum,which can be divided into D1 and D2 MSNs,originate from the lateral ganglionic eminence(LGE).Previously,we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs.Here,we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature.Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells.In addition,conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE.We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice.This suggests that,in the absence of Six3,abnormally differentiated D2 MSNs are eliminated by programmed cell death.These results further identify Six3 as an important regulatory element during D2 MSN differentiation.展开更多
The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, ...The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.展开更多
目的:通过研究运动及多巴胺II型受体(dopamine type II receptor,D2R)激动剂干预对PD模型小鼠纹状体D2MSN-D1MSN侧抑制效应的影响,揭示运动在改善PD小鼠基底神经节信息输出中的作用及机制。方法:选用4周龄雄性D2-Cre小鼠,右侧纹状体注...目的:通过研究运动及多巴胺II型受体(dopamine type II receptor,D2R)激动剂干预对PD模型小鼠纹状体D2MSN-D1MSN侧抑制效应的影响,揭示运动在改善PD小鼠基底神经节信息输出中的作用及机制。方法:选用4周龄雄性D2-Cre小鼠,右侧纹状体注射兴奋性光敏感蛋白病毒(rAAV-Ef1α-DIO-ChR2-EYFP-WPRE-pA),通过光遗传技术精准操控D2MSN。小鼠随机分为对照组(D2-Cre)和模型组,纹状体分别注射生理盐水和神经毒素6-羟基多巴胺(6-Hydroxydopamine hydrobromide,6-OHDA),经鉴定符合PD标准的模型组小鼠再分为PD组(PDD2-Cre)和PD运动组(PD+Ex D2-Cre)。采用4周匀速跑台运动(18 m/min,40 min/天,连续5天/周)和D2R激动剂分别对各组小鼠进行干预。实验结束后,制备离体脑片,利用全细胞膜片钳结合光遗传技术检测各组小鼠纹状体D2MSN-D1MSN侧抑制效应及黑质网状部的信息输出,并验证侧抑制效应的变化是否由D2R介导。结果:光刺激D2-MSN后,D1-MSN动作电位发放个数PDD2-Cre组显著低于D2-Cre组(P<0.05);PD+ExD2-Cre组显著高于PDD2-Cre组,但仍低于D2-Cre组(P<0.05)。光刺激D2-MSN诱发D1-MSN抑制性突触后电流(Optogenetic stimulation evoked inhibitory postsynaptic currents,oIPSC)的幅值与基线比值,PDD2-Cre组显著高于D2-Cre组(P<0.05),PD+ExD2-Cre组显著低于PDD2-Cre组,但高于D2-Cre组(P<0.05);光刺激D2-MSN诱发黑质网状部(SNr)抑制性突触后场电位(field inhibitory post synaptic potential,fIPSP)最大幅值,PDD2-Cre组显著低于D2-Cre组(P<0.05),PD+ExD2-Cre组显著高于PDD2-Cre组,但低于D2-Cre组(P<0.05)。结论:PD模型小鼠纹状体D2MSN-D1MSN侧抑制效应异常,并影响了SNr的信息输出,这可能是导致PD基底神经节功能紊乱的重要原因之一。4周运动干预通过改善PD模型小鼠纹状体D2MSN-D1MSN侧抑制效应,调节了SNr的信息输出。D2R在运动改善PD小鼠纹状体D2MSN-D1MSN侧抑制效应和调节基底神经节信息输出中起重要作用。展开更多
γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is respo...γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.展开更多
Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a sin...Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1(D1)receptor(D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was disrupted.Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice,but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.展开更多
基金supported by University of Florence RICATEN 2023 to EC.Grant/Award Numbers 58514_InternazionalizzazioneUniversity of Florence,to EC.Parkinson’s UK,Grant/Award Number:H-0902 to AJGWellcome Trust,Grant/Award Number:0926/Z/10/Z to AJG。
文摘During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.
文摘Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.
基金supported by the National Natural Science Foundation of China(32130044,31630029,32171094,and 32100930)the National Key Research and Development Program of China(2021ZD0202500).
文摘Autapses selectively form in specific cell types in many brain regions.Previous studies have also found putative autapses in principal spiny projection neurons(SPNs)in the striatum.However,it remains unclear whether these neurons indeed form physiologically functional autapses.We applied whole-cell recording in striatal slices and identified autaptic cells by the occurrence of prolonged asynchronous release(AR)of neurotransmitters after bursts of high-frequency action potentials(APs).Surprisingly,we found no autaptic AR in SPNs,even in the presence of Sr^(2+).However,robust autaptic AR was recorded in parvalbumin(PV)-expressing neurons.The autaptic responses were mediated by GABA_(A) receptors and their strength was dependent on AP frequency and number.Further computer simulations suggest that autapses regulate spiking activity in PV cells by providing self-inhibition and thus shape network oscillations.Together,our results indicate that PV neurons,but not SPNs,form functional autapses,which may play important roles in striatal functions.
基金the National Key Research and Development Program of China(2018YFAO 108000)the National Natural Science Foundation of China(31630032,81974175,and 31820103006)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01).
文摘Medium spiny neurons(MSNs)in the striatum,which can be divided into D1 and D2 MSNs,originate from the lateral ganglionic eminence(LGE).Previously,we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs.Here,we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature.Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells.In addition,conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE.We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice.This suggests that,in the absence of Six3,abnormally differentiated D2 MSNs are eliminated by programmed cell death.These results further identify Six3 as an important regulatory element during D2 MSN differentiation.
基金supported by grants from the National Key Research and Development Program of China (2016YFA0100702 and 2016YFC0902502)the National Natural Science Foundation of China (31670789 and 31671316)the CAMS Innovation Fund for Medical Sciences (CIFMS, 2016I2M-2-001, 2016-I2M-1-001, 2016-I2M-1-004 and 2017-I2M-1004)
文摘The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.
基金the programs for the postdoctoral fellowships-Chilean CONICYT-FONDECYT#3140218,Mexican CONACYT#164978 and DID-UACh S-2015-81Sistema Nacional de Investigadores#58512 to Abraham Rosas-Arellano+2 种基金supported by USACH PhD fellowshipsupported with a PhD fellowship from CONACYT(#299627)FONDECYT grants 1151206 and 1110571 to Maite A.Castro
文摘γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as GABAA and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of GABAA receptors,including tonic subunits.The studies about of GABAA tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.
基金the National Natural Science Foundation of China(81971285,11727813)the Fundamental Research Funds for the Central Universities(GK202005001),Shaanxi Normal University.
文摘Plasticity in the glutamatergic synapses on striatal medium spiny neurons(MSNs)is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse.Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment.In the present work,we found that the negative reinforcement learning,escaping mild foot-shocks by correct nose-poking,was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice.Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1(D1)receptor(D1-MSNs).However,24 h after the cocaine exposure,the potentiation required for reinforcement learning was disrupted.Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice,but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine.The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.
