R Gutiérrez Fuster, A León, G I Aparicio, F Brizuela Sotelo, C Scorticati
The mechanisms underlying neuronal development and synaptic formation in the brain depend on intricate cellular and molecular processes. The neuronal membrane glycoprotein GPM6a promotes neurite elongation, filopodia/spine formation, and synapse development, yet its molecular mechanisms remain unknown. Since the extracellular domains of GPM6a (ECs) command its function, we investigated the interaction between ICAM5, the neuronal member of the intercellular adhesion molecule (ICAM) family, and GPM6a's ECs. Our study aimed to explore the functional relationship between GPM6a and ICAM5 in hippocampal culture neurons and cell lines. Immunostaining of 15 days in vitro (DIV) neurons revealed significant co-localization between endogenous GPM6a clusters and ICAM5 clusters in the dendritic shaft. These results were further corroborated by overexpressing GPM6a and ICAM5 in N2a cells and hippocampal neurons at 5 DIV. Moreover, results from the co-immunoprecipitations and cell aggregation assays prove the cis and trans interaction between both proteins in GPM6a/ICAM5 overexpressing HEK293 cells. Additionally, GPM6a and ICAM5 overexpression additively enhanced neurite length, the number of neurites in N2a cells, and filopodia formation in 5 DIV neurons, indicating their cooperative role. These findings highlight the dynamic association between GPM6a and ICAM5 during neuronal development, offering insights into their contributions to neurite outgrowth, filopodia formation, and cell-cell interactions.
{"title":"Combined additive effects of neuronal membrane glycoprotein GPM6a and the intercellular cell adhesion molecule ICAM5 on neuronal morphogenesis.","authors":"R Gutiérrez Fuster, A León, G I Aparicio, F Brizuela Sotelo, C Scorticati","doi":"10.1111/jnc.16231","DOIUrl":"https://doi.org/10.1111/jnc.16231","url":null,"abstract":"<p><p>The mechanisms underlying neuronal development and synaptic formation in the brain depend on intricate cellular and molecular processes. The neuronal membrane glycoprotein GPM6a promotes neurite elongation, filopodia/spine formation, and synapse development, yet its molecular mechanisms remain unknown. Since the extracellular domains of GPM6a (ECs) command its function, we investigated the interaction between ICAM5, the neuronal member of the intercellular adhesion molecule (ICAM) family, and GPM6a's ECs. Our study aimed to explore the functional relationship between GPM6a and ICAM5 in hippocampal culture neurons and cell lines. Immunostaining of 15 days in vitro (DIV) neurons revealed significant co-localization between endogenous GPM6a clusters and ICAM5 clusters in the dendritic shaft. These results were further corroborated by overexpressing GPM6a and ICAM5 in N2a cells and hippocampal neurons at 5 DIV. Moreover, results from the co-immunoprecipitations and cell aggregation assays prove the cis and trans interaction between both proteins in GPM6a/ICAM5 overexpressing HEK293 cells. Additionally, GPM6a and ICAM5 overexpression additively enhanced neurite length, the number of neurites in N2a cells, and filopodia formation in 5 DIV neurons, indicating their cooperative role. These findings highlight the dynamic association between GPM6a and ICAM5 during neuronal development, offering insights into their contributions to neurite outgrowth, filopodia formation, and cell-cell interactions.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The five-choice serial reaction time task (5CSRTT) is a test of attention that provides a well-validated ancillary measure of impulsive action, measured by premature responses. The task has been adapted for mice in touchscreen operant boxes, which is thought to offer improved test-retest reliability. Few studies have assessed the long-term stability of performance, including premature responding in this version of the task. We used the touchscreen 5CSRTT to conduct longitudinal testing of stability of premature responding following repeated behavioral and pharmacological manipulations. Male C57BL/6J mice were trained on a baseline version of the 5CSRTT. They were then tested on versions of the task in which the stimulus duration was reduced, and inter-trial intervals were elongated or varied within-session. Premature responding was subsequently tested following administration of pharmacological agents known to bi-directionally affect attention and impulsive action-cocaine, atomoxetine, and yohimbine. Mice were lastly re-tested 6 months later using the 5CSRTT with elongated inter-trial intervals. A reduced stimulus duration impacted attention, with reduced accuracy and increased omissions, but had no effect on premature responding. Both elongating and varying the inter-trial interval within-session increased premature responses. Mice showed similar and stable levels of increased premature responding 6 months later. Cocaine increased premature responding, though less than previously reported in rats. Atomoxetine reduced premature responding. Yohimbine had no effect on premature responding in the baseline task but decreased premature responding when tested using an elongated inter-trial interval. Overall, these results highlight that the touch screen adaptation of the 5CSRTT is an effective method for longitudinal testing of attention and impulsive action and remains sensitive to performance changes arising from repeated pharmacological and behavioral challenges.
{"title":"Assessing the stability of responding of male mice in the touchscreen 5 choice serial reaction time task: Focus on premature responding.","authors":"Arya Rahbarnia, Andrew R Abela, Paul J Fletcher","doi":"10.1111/jnc.16232","DOIUrl":"https://doi.org/10.1111/jnc.16232","url":null,"abstract":"<p><p>The five-choice serial reaction time task (5CSRTT) is a test of attention that provides a well-validated ancillary measure of impulsive action, measured by premature responses. The task has been adapted for mice in touchscreen operant boxes, which is thought to offer improved test-retest reliability. Few studies have assessed the long-term stability of performance, including premature responding in this version of the task. We used the touchscreen 5CSRTT to conduct longitudinal testing of stability of premature responding following repeated behavioral and pharmacological manipulations. Male C57BL/6J mice were trained on a baseline version of the 5CSRTT. They were then tested on versions of the task in which the stimulus duration was reduced, and inter-trial intervals were elongated or varied within-session. Premature responding was subsequently tested following administration of pharmacological agents known to bi-directionally affect attention and impulsive action-cocaine, atomoxetine, and yohimbine. Mice were lastly re-tested 6 months later using the 5CSRTT with elongated inter-trial intervals. A reduced stimulus duration impacted attention, with reduced accuracy and increased omissions, but had no effect on premature responding. Both elongating and varying the inter-trial interval within-session increased premature responses. Mice showed similar and stable levels of increased premature responding 6 months later. Cocaine increased premature responding, though less than previously reported in rats. Atomoxetine reduced premature responding. Yohimbine had no effect on premature responding in the baseline task but decreased premature responding when tested using an elongated inter-trial interval. Overall, these results highlight that the touch screen adaptation of the 5CSRTT is an effective method for longitudinal testing of attention and impulsive action and remains sensitive to performance changes arising from repeated pharmacological and behavioral challenges.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sanghee Yun, Frederico C Kiffer, Grace L Bancroft, Caterina S Guzman, Ivan Soler, Harley A Haas, Raymon Shi, Riya Patel, Jaysen Lara-Jiménez, Priya L Kumar, Fionya H Tran, Kyung Jin Ahn, Yuying Rong, Krishna Luitel, Jerry W Shay, Amelia J Eisch
Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound (CDDO-EA) mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received CDDO-EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: (1) location discrimination reversal (tests behavior pattern separation and cognitive flexibility, abilities reliant on the dentate gyrus) and (2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment's end (14.25-month post-IRR), an index relevant to neurogenesis was quantified (doublecortin-immunoreactive [DCX+] dentate gyrus immature neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. One radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had slower stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice showed normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change relevant to neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.
{"title":"The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: Implications for deep space missions, female crews, and potential antioxidant countermeasures.","authors":"Sanghee Yun, Frederico C Kiffer, Grace L Bancroft, Caterina S Guzman, Ivan Soler, Harley A Haas, Raymon Shi, Riya Patel, Jaysen Lara-Jiménez, Priya L Kumar, Fionya H Tran, Kyung Jin Ahn, Yuying Rong, Krishna Luitel, Jerry W Shay, Amelia J Eisch","doi":"10.1111/jnc.16225","DOIUrl":"10.1111/jnc.16225","url":null,"abstract":"<p><p>Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment are lacking. We asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound (CDDO-EA) mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received CDDO-EA (400 μg/g of food) or a control diet (vehicle, Veh) for 5 days and Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: (1) location discrimination reversal (tests behavior pattern separation and cognitive flexibility, abilities reliant on the dentate gyrus) and (2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment's end (14.25-month post-IRR), an index relevant to neurogenesis was quantified (doublecortin-immunoreactive [DCX+] dentate gyrus immature neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. One radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had slower stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice showed normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change relevant to neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reactive astrocyte activation in the context of cerebral ischemia/reperfusion (I/R) injury gives rise to two distinct subtypes: the neurotoxic A1 type and the neuroprotective A2 type. DJ-1 (Parkinson disease protein 7, PARK7), originally identified as a Parkinson's disease-associated protein, is a multifunctional anti-oxidative stress protein with molecular chaperone and signaling functions. SHP-1 (Src homology 2 domain-containing phosphatase-1) is a protein tyrosine phosphatase closely associated with cellular signal transduction. miR-155 is a microRNA that participates in cellular functions by regulating gene expression. Recent studies have uncovered the relationship between DJ-1 and astrocyte-mediated neuroprotection, which may be related to its antioxidant properties and regulation of signaling molecules such as SHP-1. Furthermore, miR-155 may exert its effects by influencing SHP-1, providing a potential perspective for understanding the molecular mechanisms of stroke. A middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reperfusion (OGD/R) model were established to simulate focal cerebral I/R injury in vivo and in vitro, respectively. The in vivo interaction between DJ-1 and SHP-1 has been experimentally validated through immunoprecipitation. Overexpression of DJ-1 attenuates I/R injury and suppresses miR-155 expression. In addition, inhibition of miR-155 upregulates SHP-1 expression and modulates astrocyte activation phenotype. These findings suggest that DJ-1 mediates astrocyte activation via the miR-155/SHP-1 pathway, playing a pivotal role in the pathogenesis of cerebral ischemia-reperfusion injury. Our results provide a potential way for exploring the pathogenesis of ischemic stroke and present promising targets for pharmacological intervention.
{"title":"DJ-1 regulates astrocyte activation through miR-155/SHP-1 signaling in cerebral ischemia/reperfusion injury.","authors":"Ying Xue, Yuan Wang, Tianyi Chen, Li Peng, Chenglong Wang, Guijun Xue, Shanshan Yu","doi":"10.1111/jnc.16230","DOIUrl":"https://doi.org/10.1111/jnc.16230","url":null,"abstract":"<p><p>Reactive astrocyte activation in the context of cerebral ischemia/reperfusion (I/R) injury gives rise to two distinct subtypes: the neurotoxic A1 type and the neuroprotective A2 type. DJ-1 (Parkinson disease protein 7, PARK7), originally identified as a Parkinson's disease-associated protein, is a multifunctional anti-oxidative stress protein with molecular chaperone and signaling functions. SHP-1 (Src homology 2 domain-containing phosphatase-1) is a protein tyrosine phosphatase closely associated with cellular signal transduction. miR-155 is a microRNA that participates in cellular functions by regulating gene expression. Recent studies have uncovered the relationship between DJ-1 and astrocyte-mediated neuroprotection, which may be related to its antioxidant properties and regulation of signaling molecules such as SHP-1. Furthermore, miR-155 may exert its effects by influencing SHP-1, providing a potential perspective for understanding the molecular mechanisms of stroke. A middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reperfusion (OGD/R) model were established to simulate focal cerebral I/R injury in vivo and in vitro, respectively. The in vivo interaction between DJ-1 and SHP-1 has been experimentally validated through immunoprecipitation. Overexpression of DJ-1 attenuates I/R injury and suppresses miR-155 expression. In addition, inhibition of miR-155 upregulates SHP-1 expression and modulates astrocyte activation phenotype. These findings suggest that DJ-1 mediates astrocyte activation via the miR-155/SHP-1 pathway, playing a pivotal role in the pathogenesis of cerebral ischemia-reperfusion injury. Our results provide a potential way for exploring the pathogenesis of ischemic stroke and present promising targets for pharmacological intervention.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lidia Miguel Telega, Danesh Ashouri Vajari, Chockalingam Ramanathan, Volker A Coenen, Máté D Döbrössy
Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS.
内侧前脑束深部脑刺激(MFB-DBS)可对治疗耐受性抑郁症(TRD)患者产生快速而持久的抗抑郁效果。其机制尚不十分清楚,但有一种假设认为,多巴胺能(DAergic)纤维的调节有助于治疗效果。已经研究了急性 DBS 对 DA 释放的影响,但还缺乏急性重复性 DBS 的纵向研究。在对行为动物和非行为动物进行急性和重复性刺激后的 8 周内,我们使用纤维光度计测量了 Long-Evans accumbal DA 释放和腹侧被盖区(VTA)钙离子对不同 mfb-DBS 参数的强直性和相位性信号传导。随着频率和 DBS 持续时间的增加,在两个目标中都观察到了 DBS 诱导的释放。随着时间的推移,130 Hz 刺激会增加相性和强直性 DA 反应,后者是其长期临床有效性的潜在机制。VTA钙离子瞬时降低,而相性活动随频率增加而增加。脉宽(PW)介导的峰值释放时间差异也表明,它可能会平行激活不同的纤维类型。此外,在高架迷宫(EPM)过程中,DA瞬时率的降低表明DA的释放与环境和刺激持续时间有关。这些数据证实了慢性反向/正向 DAergic 反应与刺激参数相关的可变性,为 mfb DBS 的时间适应性、连接性和纤维招募提供了新的见解。
{"title":"Chronic in vivo sequelae of repetitive acute mfb-DBS on accumbal dopamine and midbrain neuronal activity.","authors":"Lidia Miguel Telega, Danesh Ashouri Vajari, Chockalingam Ramanathan, Volker A Coenen, Máté D Döbrössy","doi":"10.1111/jnc.16223","DOIUrl":"https://doi.org/10.1111/jnc.16223","url":null,"abstract":"<p><p>Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda Schneeweis, Dawson Hillyer, Tsering Lama, Daeun Kim, Charles Palka, Sarra Djemil, Mai Abdel-Ghani, Kelly Mandella, William Zhu, Nicole Alvarez, Lara Stefansson, Robert Yasuda, Junfeng Ma, Daniel T S Pak
Tau is a microtubule-associated protein implicated in Alzheimer's disease (AD) and other neurodegenerative disorders termed tauopathies. Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill-defined term, obscuring the functional importance of specific sites in different physiological or pathological settings. Here, we focused on global mapping of tau phosphorylation specifically during conditions of neuronal hyperexcitation. Hyperexcitation is a property of AD and other tauopathies linked to human cognitive deficits and increased risk of developing seizures and epilepsy. Moreover, hyperexcitation promotes extracellular secretion and trans-synaptic propagation of tau. Using unbiased mass spectrometry, we identified a novel phosphorylation signature in the C-terminal domain of tau detectable only during neuronal hyperactivity in primary cultured rat hippocampal neurons. These sites influenced tau localization to dendrites as well as the size of excitatory postsynaptic sites. These results demonstrate novel physiological tau functions at synapses and the utility of comprehensive analysis of tau phosphorylation during specific signaling contexts.
Tau 是一种微管相关蛋白,与阿尔茨海默病(AD)和其他神经退行性疾病(称为 tauopathies)有关。病理上,tau的聚集形式会形成神经纤维缠结(NFT),损害其稳定微管的能力并促进神经毒性。事实上,神经纤维缠结与神经元丧失和认知障碍有关。tau的高磷酸化可见于所有tau病,并反映了疾病的进展,这表明它在发病机制中起着至关重要的作用。然而,高磷酸化仍然是一个定义不清的通用术语,模糊了特定位点在不同生理或病理环境中的功能重要性。在这里,我们重点研究了神经元过度兴奋条件下 tau 磷酸化的全局图谱。过度兴奋是注意力缺失症和其他与人类认知缺陷以及癫痫发作和癫痫风险增加有关的 tau 病的一种特性。此外,过度兴奋还会促进细胞外分泌和 tau 的跨突触传播。通过无偏质谱分析,我们在原代培养的大鼠海马神经元中发现了一种仅在神经元过度兴奋时才能检测到的新型磷酸化特征。这些位点影响了 tau 在树突上的定位以及兴奋性突触后位点的大小。这些结果证明了tau在突触处的新生理功能,以及在特定信号背景下对tau磷酸化进行全面分析的实用性。
{"title":"Mass spectrometry identifies tau C-terminal phosphorylation cluster during neuronal hyperexcitation.","authors":"Amanda Schneeweis, Dawson Hillyer, Tsering Lama, Daeun Kim, Charles Palka, Sarra Djemil, Mai Abdel-Ghani, Kelly Mandella, William Zhu, Nicole Alvarez, Lara Stefansson, Robert Yasuda, Junfeng Ma, Daniel T S Pak","doi":"10.1111/jnc.16221","DOIUrl":"https://doi.org/10.1111/jnc.16221","url":null,"abstract":"<p><p>Tau is a microtubule-associated protein implicated in Alzheimer's disease (AD) and other neurodegenerative disorders termed tauopathies. Pathological, aggregated forms of tau form neurofibrillary tangles (NFTs), impairing its ability to stabilize microtubules and promoting neurotoxicity. Indeed, NFTs correlate with neuronal loss and cognitive impairment. Hyperphosphorylation of tau is seen in all tauopathies and mirrors disease progression, suggesting an essential role in pathogenesis. However, hyperphosphorylation remains a generic and ill-defined term, obscuring the functional importance of specific sites in different physiological or pathological settings. Here, we focused on global mapping of tau phosphorylation specifically during conditions of neuronal hyperexcitation. Hyperexcitation is a property of AD and other tauopathies linked to human cognitive deficits and increased risk of developing seizures and epilepsy. Moreover, hyperexcitation promotes extracellular secretion and trans-synaptic propagation of tau. Using unbiased mass spectrometry, we identified a novel phosphorylation signature in the C-terminal domain of tau detectable only during neuronal hyperactivity in primary cultured rat hippocampal neurons. These sites influenced tau localization to dendrites as well as the size of excitatory postsynaptic sites. These results demonstrate novel physiological tau functions at synapses and the utility of comprehensive analysis of tau phosphorylation during specific signaling contexts.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Retraction: M. C. Liu, V. Akle, W. Zheng, J. Kitlen, B. O'Steen, S. F. Larner, J. R. Dave, F. C. Tortella, R. L. Hayes, and K. K. W. Wang, "Extensive Degradation of Myelin Basic Protein Isoforms by Calpain Following Traumatic Brain Injury," Journal of Neurochemistry 98, no. 3 (2006): 700-712. https://doi.org/10.1111/j.1471-4159.2006.03882.x. The above article, published online on 19 June 2006, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley and Sons Ltd. A third party reported that they had detected evidence of image manipulation and duplication throughout the published article. An investigation by the publisher and the editors concluded that there was evidence of splicing in Figures 2a, 2b, 3a, 5a, 6a, and 8a. The investigation also found duplications of lanes in Figures 3a, 3d, and 4a. Lastly, the investigation found that the same actin blots in Figure 3 have been used in two other articles by many of the same authors, despite representing different experimental conditions. The authors did not respond to an inquiry by the publisher. The retraction has been agreed to because the results presented in the article can no longer be considered reliable. The authors did not respond to the notice of retraction.
撤回:M. C. Liu, V. Akle, W. Zheng, J. Kitlen, B. O'Steen, S. F. Larner, J. R. Dave, F. C. Tortella, R. L. Hayes, and K. K. W. Wang, "Extensive Degradation of Myelin Basic Protein Isoforms by Calpain Following Traumatic Brain Injury," Journal of Neurochemistry 98, no.3 (2006):700-712。https://doi.org/10.1111/j.1471-4159.2006.03882.x。上述文章于 2006 年 6 月 19 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),经期刊主编 Andrew Lawrence、国际神经化学学会和 John Wiley and Sons Ltd.协商,该文章已被撤回。第三方报告称,他们在已发表的文章中发现了篡改和复制图片的证据。出版商和编辑调查后认为,图 2a、2b、3a、5a、6a 和 8a 中存在拼接的证据。调查还发现图 3a、图 3d 和图 4a 中的泳道存在重复。最后,调查发现图 3 中相同的肌动蛋白印迹被许多相同的作者用在了另外两篇文章中,尽管代表了不同的实验条件。作者没有回复出版商的询问。由于文章中的结果不再可靠,因此同意撤稿。作者未对撤稿通知做出回应。
{"title":"RETRACTION: Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury.","authors":"","doi":"10.1111/jnc.16229","DOIUrl":"https://doi.org/10.1111/jnc.16229","url":null,"abstract":"<p><p>Retraction: M. C. Liu, V. Akle, W. Zheng, J. Kitlen, B. O'Steen, S. F. Larner, J. R. Dave, F. C. Tortella, R. L. Hayes, and K. K. W. Wang, \"Extensive Degradation of Myelin Basic Protein Isoforms by Calpain Following Traumatic Brain Injury,\" Journal of Neurochemistry 98, no. 3 (2006): 700-712. https://doi.org/10.1111/j.1471-4159.2006.03882.x. The above article, published online on 19 June 2006, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Andrew Lawrence; the International Society for Neurochemistry; and John Wiley and Sons Ltd. A third party reported that they had detected evidence of image manipulation and duplication throughout the published article. An investigation by the publisher and the editors concluded that there was evidence of splicing in Figures 2a, 2b, 3a, 5a, 6a, and 8a. The investigation also found duplications of lanes in Figures 3a, 3d, and 4a. Lastly, the investigation found that the same actin blots in Figure 3 have been used in two other articles by many of the same authors, despite representing different experimental conditions. The authors did not respond to an inquiry by the publisher. The retraction has been agreed to because the results presented in the article can no longer be considered reliable. The authors did not respond to the notice of retraction.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yoshiatsu Aomine, Yuto Shimo, Koki Sakurai, Mayuka Abe, Tom Macpherson, Takaaki Ozawa, Takatoshi Hikida
Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex‐dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein–protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic‐related genes in males and increased expression of innate immunity‐related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex‐dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.image
{"title":"Sex‐dependent differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice","authors":"Yoshiatsu Aomine, Yuto Shimo, Koki Sakurai, Mayuka Abe, Tom Macpherson, Takaaki Ozawa, Takatoshi Hikida","doi":"10.1111/jnc.16227","DOIUrl":"https://doi.org/10.1111/jnc.16227","url":null,"abstract":"Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex‐dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein–protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic‐related genes in males and increased expression of innate immunity‐related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex‐dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/jnc16227-fig-0008-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yigong Wei, Kun Zhou, Cheng Wang, Xiaolin Du, Zhengdi Wang, Guangtang Chen, Huan Zhang, Xuhui Hui
Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1‐polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA‐142‐3p (miR‐142‐3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit‐8 (CCK‐8), colony formation assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR‐142‐3p and M1 exosomes affect GBM progression. Upregulation of miR‐142‐3p expression was detected in M1‐polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR‐142‐3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR‐142‐3p inhibits GBM cell growth via targeting high‐mobility group box 1 (HMGB1). In addition, miR‐142‐3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death‐1/programmed death ligand‐1 (PD‐1/PD‐L1) checkpoint. Our study demonstrated that exosomal miR‐142‐3p from M1‐polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1‐mediated PD‐1/PD‐L1 checkpoint.image
{"title":"Exosomal miR‐142‐3p from M1‐polarized macrophages suppresses cell growth and immune escape in glioblastoma through regulating HMGB1‐mediated PD‐1/PD‐L1 checkpoint","authors":"Yigong Wei, Kun Zhou, Cheng Wang, Xiaolin Du, Zhengdi Wang, Guangtang Chen, Huan Zhang, Xuhui Hui","doi":"10.1111/jnc.16224","DOIUrl":"https://doi.org/10.1111/jnc.16224","url":null,"abstract":"Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1‐polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA‐142‐3p (miR‐142‐3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit‐8 (CCK‐8), colony formation assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR‐142‐3p and M1 exosomes affect GBM progression. Upregulation of miR‐142‐3p expression was detected in M1‐polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR‐142‐3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR‐142‐3p inhibits GBM cell growth via targeting high‐mobility group box 1 (HMGB1). In addition, miR‐142‐3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death‐1/programmed death ligand‐1 (PD‐1/PD‐L1) checkpoint. Our study demonstrated that exosomal miR‐142‐3p from M1‐polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1‐mediated PD‐1/PD‐L1 checkpoint.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/jnc16224-fig-0006-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR1–5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.image
{"title":"Deciphering the role of sphingosine 1‐phosphate in central nervous system myelination and repair","authors":"Fatima Binish, Junhua Xiao","doi":"10.1111/jnc.16228","DOIUrl":"https://doi.org/10.1111/jnc.16228","url":null,"abstract":"Sphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR<jats:sub>1–5</jats:sub>). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/jnc16228-fig-0002-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}