Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrev...Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrevin-binding protein 1） gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-lC isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyms, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-l-deficient sandy （sdy） mice （a mouse model of SCZ） is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3- II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-lC. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin- 1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin- 1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.展开更多
BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state,...BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state, thereby inhibiting abnormal epileptic discharges, and eventually controlling epileptic seizure. OBJECTIVE： This study was designed to observe the effects of chaotic electrical stimulation to the subthalamic nucleus on mossy fiber sprouting, epileptic seizures, and electrical discharges, and to summarize the most suitable intervention. DESIGN, TIME AND SETTING： This randomized grouping, neuroelectrophysiological study was performed at the Laboratory of Neurology, Union Hospital Affiliated to Fujian Medical University in September 2007. MATERIALS： Fifty-five healthy, male, Sprague Dawley rats were subjected to an epileptic model by an intraperitoneal injection of pentylenetetrazol. The YC-2 programmed electrical stimulator was provided by Chengdu Instrument Factory, China; the video electroencephalographic system （KT-88-2400） and 24-hour active electroencephalographic system were products of Contec Medical System Co., Ltd., China; pentylenetetrazol was purchased from Sigma, USA. METHODS： The present interventional method consisted of electrical stimulation to the subthalamic nucleus with an intensity of 500 μA, pulse width 0.05 ms, frequency 30 Hz, and a duration of 20 minutes for 14 successive days. Fifty-five rats were divided into 6 groups： （1） pre-stimulation （n = 10）, pentylenetetrazol was administered and 30 minutes later, chaotic electrical stimulation was performed; （2） synchronous stimulation （n = 10）, rats received pentylenetetrazol and chaotic electrical stimulation concurrently; （3） post-administration stimulation （n = 10）, after pentylenetetrazol administration, chaotic electrical stimulation was performed immediately after cessation of a seizure; （4） sham-stimulation （n = 10）, following pentylenetetrazol administration, an electrode was connected to the stimulator, but electrical stimulation was not performed; （5） control （n = 10）, pentylenetetrazol administration, but no electrode was implanted; （6） blank control （n = 50）, administration of the same amount of physiological saline and chaotic electrical stimulation. MAIN OUTCOME MEASURES： Timm-stained granule change was scored. Simultaneously, electroencephalography was performed to acquire seizure counts and time course of epileptic discharge within 24 hours. RESULTS： Timm scores were lower in the electrically stimulated rats than in the non-stimulated rats （P 〈 0.01）. Timm scores were lowest in the synchronous stimulation group. When the rats suffered from tonic clonic seizure, the electroencephalogram primarily showed a persistent spike-slow wave and sharp wave. For the electrically stimulated rats, the mean values of seizure counts and time course of epileptic discharge during each hour were noticeably decreased compared with the non-stimulated rats. The synchronous stimulation group, however, had the lowest seizure counts and the shortest time course, followed by the pre-stimulation group, and lastly the post-administration stimulation group. Significant differences existed among the groups （P 〈 0.01）. Compared with the pre-stimulation group and the post-administration stimulation group, the latent period of grades Ⅰ and Ⅳ epileptic seizures was significantly prolonged, and the time course of tonic clonic seizure, as well as total time course, were significantly shortened in the synchronous stimulation group （P 〈 0.01）. CONCLUSION： Simultaneous administration of pentylenetetrazol together with chaotic electrical stimulation produced the greatest inhibitory effects on epileptic seizures. This is possibly related to inhibition of abnormal mossy fiber spouting in the hippocampus.展开更多
Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate g...Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate gyrus causes the synaptic reorganization in the hippocampus, which is an important cause of temporal lobe epilepsy in animals and humans. It is also essential to the genesis and development of epilepsy. As the predominant excitatory neurotransmitter in the central nervous system, glutamate plays a role in synaptic reorganization and development of epilepsy.展开更多
Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogen...Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogenesis and progression of epilepsy,but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown.This study aimed to investigate the effect of ATN-DBS on MFS,as well as potential signaling pathways by a kainic acid(KA)-induced epileptic model.Methods:Twenty-four rhesus monkeys were randomly assigned to control,epilepsy(EP),EP-sham-DBS,and EP-DBS groups.KA was injected to establish the chronic epileptic model.The left ATN was implanted with a DBS lead and stimulated for 8 weeks.Enzyme-linked immunosorbent assay,Western blotting,and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus.One-way analysis of variance,followed by the Tukeypost hoc correction,was used to analyze the statistical significance of differences among multiple groups.Results:ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy.The number of ectopic granule cells was reduced in monkeys that received ATN stimulation(P<0.0001).Levels of 3′,5′-cyclic adenosine monophosphate(cAMP)and protein kinase A(PKA)in the hippocampus,together with Akt phosphorylation,were noticeably reduced in monkeys that received ATN stimulation(P=0.0030 andP=0.0001,respectively).ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions(allP<0.0001).Conclusion:ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells,which may be associated with the reduced MFS in chronic epilepsy.The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.展开更多
The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendr...The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Here,through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1~(fl/fl)with Emx1-Cre and Nex-Cre,respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.展开更多
Located in the southeastern parts of the BaouléMossi domain of the West African Craton,the Birimian terrane in Ghana is known to consist of predominantly juvenile crust emplaced during the Eburnean orogeny.Here w...Located in the southeastern parts of the BaouléMossi domain of the West African Craton,the Birimian terrane in Ghana is known to consist of predominantly juvenile crust emplaced during the Eburnean orogeny.Here we present novel coupled zircon U-Pb and Lu-Hf isotope data from nine Birimian granitoids intruding different domains from northwestern,western and southeastern Ghana.Sub-chondriticε_(Hf)-values indicating reworking of Archaean crust are recorded in zircon from both northwestern and southeastern Ghana.As a conservative estimate 71%of all analysed zircon grains spanning in age from2220 Ma to 2130 Ma require contribution from a reworked Archaean source,contradicting the common belief that the Birimian terrane consist of predominantly juvenile crust.A minimumε_(Hf)-value of-10.5 at2139 Ma suggests a Palaeoarchaean to late Mseoarchaean component as the contributing ancient source.Combined with previously reported heavy zirconδ^(18)O signatures from Birimian river zircon in Ghana,our new data suggests reworking of Archaean aged sediments during subduction initiated crustal growth in the vicinity of one,or possibly in between two Archaean aged cratons.展开更多
基金partially supported by grants from the National Natural Science Foundation of China(Nos.91332116 and 31230046)the National Basic Research Program of China(No.2014CB942803)Chinese Academy of Sciences(No.KJZD-EW-L08)
文摘Schizophrenia （SCZ） is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 （dystrobrevin-binding protein 1） gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-lC isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyms, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-l-deficient sandy （sdy） mice （a mouse model of SCZ） is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3- II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-lC. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin- 1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin- 1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
基金Research and Development Foundation of Fujian Medical University, No. FJGXY04041
文摘BACKGROUND： Previous studies have demonstrated that appropriate interventions can alter brain electrical activity of epileptic patients prior to and during a seizure, leading to maintenance of a highly chaotic state, thereby inhibiting abnormal epileptic discharges, and eventually controlling epileptic seizure. OBJECTIVE： This study was designed to observe the effects of chaotic electrical stimulation to the subthalamic nucleus on mossy fiber sprouting, epileptic seizures, and electrical discharges, and to summarize the most suitable intervention. DESIGN, TIME AND SETTING： This randomized grouping, neuroelectrophysiological study was performed at the Laboratory of Neurology, Union Hospital Affiliated to Fujian Medical University in September 2007. MATERIALS： Fifty-five healthy, male, Sprague Dawley rats were subjected to an epileptic model by an intraperitoneal injection of pentylenetetrazol. The YC-2 programmed electrical stimulator was provided by Chengdu Instrument Factory, China; the video electroencephalographic system （KT-88-2400） and 24-hour active electroencephalographic system were products of Contec Medical System Co., Ltd., China; pentylenetetrazol was purchased from Sigma, USA. METHODS： The present interventional method consisted of electrical stimulation to the subthalamic nucleus with an intensity of 500 μA, pulse width 0.05 ms, frequency 30 Hz, and a duration of 20 minutes for 14 successive days. Fifty-five rats were divided into 6 groups： （1） pre-stimulation （n = 10）, pentylenetetrazol was administered and 30 minutes later, chaotic electrical stimulation was performed; （2） synchronous stimulation （n = 10）, rats received pentylenetetrazol and chaotic electrical stimulation concurrently; （3） post-administration stimulation （n = 10）, after pentylenetetrazol administration, chaotic electrical stimulation was performed immediately after cessation of a seizure; （4） sham-stimulation （n = 10）, following pentylenetetrazol administration, an electrode was connected to the stimulator, but electrical stimulation was not performed; （5） control （n = 10）, pentylenetetrazol administration, but no electrode was implanted; （6） blank control （n = 50）, administration of the same amount of physiological saline and chaotic electrical stimulation. MAIN OUTCOME MEASURES： Timm-stained granule change was scored. Simultaneously, electroencephalography was performed to acquire seizure counts and time course of epileptic discharge within 24 hours. RESULTS： Timm scores were lower in the electrically stimulated rats than in the non-stimulated rats （P 〈 0.01）. Timm scores were lowest in the synchronous stimulation group. When the rats suffered from tonic clonic seizure, the electroencephalogram primarily showed a persistent spike-slow wave and sharp wave. For the electrically stimulated rats, the mean values of seizure counts and time course of epileptic discharge during each hour were noticeably decreased compared with the non-stimulated rats. The synchronous stimulation group, however, had the lowest seizure counts and the shortest time course, followed by the pre-stimulation group, and lastly the post-administration stimulation group. Significant differences existed among the groups （P 〈 0.01）. Compared with the pre-stimulation group and the post-administration stimulation group, the latent period of grades Ⅰ and Ⅳ epileptic seizures was significantly prolonged, and the time course of tonic clonic seizure, as well as total time course, were significantly shortened in the synchronous stimulation group （P 〈 0.01）. CONCLUSION： Simultaneous administration of pentylenetetrazol together with chaotic electrical stimulation produced the greatest inhibitory effects on epileptic seizures. This is possibly related to inhibition of abnormal mossy fiber spouting in the hippocampus.
文摘Ketogenic diet （KD） is a high fat, low protein, low carbohydrate diet. Its antiepileptic effect is certain but the underlying mechanism is unknown. Mossy fiber sprouting in the inner molecular layer of the dentate gyrus causes the synaptic reorganization in the hippocampus, which is an important cause of temporal lobe epilepsy in animals and humans. It is also essential to the genesis and development of epilepsy. As the predominant excitatory neurotransmitter in the central nervous system, glutamate plays a role in synaptic reorganization and development of epilepsy.
基金National Nature Science Foundation of China(Nos.81671104,81701268,61761166004,and 81830033)Beijing Municipal Administration of Hospitals’Ascent Plan(No.DFL20150503)+1 种基金Capital Health Research and Development of Special(No.2018-2-1076)China Postdoctoral Science Foundation(No.2018T110120)。
文摘Background:Anterior thalamic nuclei(ATN)deep brain stimulation(DBS)is an effective method of controlling epilepsy,especially temporal lobe epilepsy.Mossy fiber sprouting(MFS)plays an indispensable role in the pathogenesis and progression of epilepsy,but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown.This study aimed to investigate the effect of ATN-DBS on MFS,as well as potential signaling pathways by a kainic acid(KA)-induced epileptic model.Methods:Twenty-four rhesus monkeys were randomly assigned to control,epilepsy(EP),EP-sham-DBS,and EP-DBS groups.KA was injected to establish the chronic epileptic model.The left ATN was implanted with a DBS lead and stimulated for 8 weeks.Enzyme-linked immunosorbent assay,Western blotting,and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus.One-way analysis of variance,followed by the Tukeypost hoc correction,was used to analyze the statistical significance of differences among multiple groups.Results:ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy.The number of ectopic granule cells was reduced in monkeys that received ATN stimulation(P<0.0001).Levels of 3′,5′-cyclic adenosine monophosphate(cAMP)and protein kinase A(PKA)in the hippocampus,together with Akt phosphorylation,were noticeably reduced in monkeys that received ATN stimulation(P=0.0030 andP=0.0001,respectively).ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions(allP<0.0001).Conclusion:ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells,which may be associated with the reduced MFS in chronic epilepsy.The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.
基金supported by grants from the National Natural Science Foundation of China(31930045 and 81870899)the National Key R&D Program of China(2016YFA0501001)。
文摘The Wnt signaling pathway plays key roles in various developmental processes.Wnt5a,which activates the non-canonical pathway,has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis.However,the mechanism underlying the regulation of Wnt5a remains unclear.Here,through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1~(fl/fl)with Emx1-Cre and Nex-Cre,respectively,we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated.Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus.We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site.These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.
基金Financial support provided by the Swedish Research Council(grant VR#2008-3447 and VR#2012-4531 to A.Schersten)Per Westlings minnesfond to A.Petersson
文摘Located in the southeastern parts of the BaouléMossi domain of the West African Craton,the Birimian terrane in Ghana is known to consist of predominantly juvenile crust emplaced during the Eburnean orogeny.Here we present novel coupled zircon U-Pb and Lu-Hf isotope data from nine Birimian granitoids intruding different domains from northwestern,western and southeastern Ghana.Sub-chondriticε_(Hf)-values indicating reworking of Archaean crust are recorded in zircon from both northwestern and southeastern Ghana.As a conservative estimate 71%of all analysed zircon grains spanning in age from2220 Ma to 2130 Ma require contribution from a reworked Archaean source,contradicting the common belief that the Birimian terrane consist of predominantly juvenile crust.A minimumε_(Hf)-value of-10.5 at2139 Ma suggests a Palaeoarchaean to late Mseoarchaean component as the contributing ancient source.Combined with previously reported heavy zirconδ^(18)O signatures from Birimian river zircon in Ghana,our new data suggests reworking of Archaean aged sediments during subduction initiated crustal growth in the vicinity of one,or possibly in between two Archaean aged cratons.
