主要采用DAB免疫组织化学方法对离子型谷氨酸受体AMPA亚型GluR2在成年雄性斑胸草雀(Taeniopygia guttata)鸣唱系统的分布进行了研究.结果显示:1)端脑高级发声中枢HVC(proper name)中,GluR2表达丰富,并主要分布于胞体部位;在HVC投射至弓...主要采用DAB免疫组织化学方法对离子型谷氨酸受体AMPA亚型GluR2在成年雄性斑胸草雀(Taeniopygia guttata)鸣唱系统的分布进行了研究.结果显示:1)端脑高级发声中枢HVC(proper name)中,GluR2表达丰富,并主要分布于胞体部位;在HVC投射至弓状皮质栎核(robust nucleus of the arcopallium,RA)的路径上,有大量的GluR2阳性细胞分布,并有少量阳性纤维分布;2)RA中,呈密集的GluR2阳性胞体标记;3)前脑基底神经节X区(Area X)中,有少量阳性胞体标记;4)中脑腹侧被盖区(ventral tegmental area,VTA)、黑质致密部(substantia nigra compacta,SNc)存在大量的阳性胞体标记.本实验结果表明GluR2可能参与了鸣唱运动的调控和维持.展开更多
The CC chemokine ligand 2(CCL2,also known as MCP-1)and its cognate receptor CCR2 have wellcharacterized roles in chemotaxis.CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excit...The CC chemokine ligand 2(CCL2,also known as MCP-1)and its cognate receptor CCR2 have wellcharacterized roles in chemotaxis.CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability.However,the detailed molecular mechanism underlying this process remains largely unclear.In cultured hippocampal neurons,CCL2 application rapidly upregulated surface expression of GluA1,in a CCR2-dependent manner,assayed using SEP-GluA1 live imaging,surface GluA1 antibody staining,and electrophysiology.Using pharmacology and reporter assays,we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq-and CaMKII-dependent signaling.Consistently,using i.p.injection of lipopolysaccharide to induce neuroinflammation,we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus,an effect blocked in Ccr2−/−mice.Together,these results provide a mechanism through which CCL2,and other secreted molecules that signal through G-protein coupled receptors,can directly regulate synaptic transmission.展开更多
Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY29355 8, an α amino 3 hydroxy 5 methyl 4 isox azolepropionic acid (AMPA)/kain ate (KA) receptor antagonist, is effective in preclinical models ...Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY29355 8, an α amino 3 hydroxy 5 methyl 4 isox azolepropionic acid (AMPA)/kain ate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple blind, parallel group, double d ummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneou s (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary e fficacy variable was the headache response rate, i.e. headache score improvement from mod erate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients , 44 patients (20M:24F; mean age ±.SD = 40 ±.9 years) completed the study. Res ponse rates were 69%for LY293558 (P = 0.017 vs. placebo), 86%for sumatriptan ( P < .0.01 vs. placebo) and 25%for placebo. LY293558 and sumatriptan were superi or to placebo (P < .0.01 for all comparisons) on all other measures of improveme nt in pain and migraine associated symptoms. Fifteen percent of patients who too k LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty t hree percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31%of those who received placebo reported AEs (n = 5; four mild, one severe ). The efficacy and safety results of LY293558 in this small migraine proof of c oncept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.展开更多
基金supported by the National Natural Science Foundation of China(No.30670680)the Medical Foundation for younger scholars of Xi'an Jiaotong University(No.YQN0811)
文摘晚时相长时程增强(late-phase long-term potentiation,L-LTP)对于海马长期记忆的维持具有非常重要的作用,然而L-LTP可被诱导之后的神经元活动所翻转。本实验旨在研究海马CA1区L-LTP的翻转是否有突触前机制的参与以及L-LTP翻转前后AMPARs的表达有无变化。实验采用海马脑薄片细胞外场电位记录技术,使用强直刺激(high-frequency stimulation,HFS)诱导出CA1区L-LTP,2h后用两组间隔10min的高强度的双脉冲低频刺激(high-intensity paired-pulse low frequency stimulation,HI-PP-LFS)诱导L-LTP翻转。在LTP诱导前、诱导2h后、翻转后均给予一个双脉冲刺激,观察双脉冲比值(paired-pulse ratio,PPR)的变化;另一方面,实验通过免疫荧光组织化学方法观察AMPAR/GluR2在L-LTP翻转前后海马CA1区表达的变化。结果显示,L-LTP诱导后2h,HI-PP-LFS可诱导L-LTP的部分翻转(翻转率为61.79%±14.51%)。LTP诱导前、诱导2h后、翻转后PPR均大于1,表现为双脉冲易化(paired-pulse facilitation,PPF),且三者大小顺序为:LTP诱导后<LTP翻转后<LTP诱导前;在海马CA1区AMPAR/GluR2亚单位的表达方面,对照组、LTP组及LTP翻转组之间没有显著差异。上述结果提示,海马CA1区L-LTP维持与翻转均有突触前机制的参与,但L-LTP诱导与翻转前后AMPAR/GluR2表达没有发生变化。
文摘主要采用DAB免疫组织化学方法对离子型谷氨酸受体AMPA亚型GluR2在成年雄性斑胸草雀(Taeniopygia guttata)鸣唱系统的分布进行了研究.结果显示:1)端脑高级发声中枢HVC(proper name)中,GluR2表达丰富,并主要分布于胞体部位;在HVC投射至弓状皮质栎核(robust nucleus of the arcopallium,RA)的路径上,有大量的GluR2阳性细胞分布,并有少量阳性纤维分布;2)RA中,呈密集的GluR2阳性胞体标记;3)前脑基底神经节X区(Area X)中,有少量阳性胞体标记;4)中脑腹侧被盖区(ventral tegmental area,VTA)、黑质致密部(substantia nigra compacta,SNc)存在大量的阳性胞体标记.本实验结果表明GluR2可能参与了鸣唱运动的调控和维持.
基金supported by grants from the National Natural Science Foundation of China(32030049 and 82101619)the Ministry of Science and Technology of China(2021ZD0202500)+1 种基金the Key-Area Research and Development Program of Guangdong Province(2019B030335001)the Qidong-SLS Innovation Fund(to X.Y.)。
文摘The CC chemokine ligand 2(CCL2,also known as MCP-1)and its cognate receptor CCR2 have wellcharacterized roles in chemotaxis.CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability.However,the detailed molecular mechanism underlying this process remains largely unclear.In cultured hippocampal neurons,CCL2 application rapidly upregulated surface expression of GluA1,in a CCR2-dependent manner,assayed using SEP-GluA1 live imaging,surface GluA1 antibody staining,and electrophysiology.Using pharmacology and reporter assays,we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq-and CaMKII-dependent signaling.Consistently,using i.p.injection of lipopolysaccharide to induce neuroinflammation,we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus,an effect blocked in Ccr2−/−mice.Together,these results provide a mechanism through which CCL2,and other secreted molecules that signal through G-protein coupled receptors,can directly regulate synaptic transmission.
文摘Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY29355 8, an α amino 3 hydroxy 5 methyl 4 isox azolepropionic acid (AMPA)/kain ate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple blind, parallel group, double d ummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneou s (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary e fficacy variable was the headache response rate, i.e. headache score improvement from mod erate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients , 44 patients (20M:24F; mean age ±.SD = 40 ±.9 years) completed the study. Res ponse rates were 69%for LY293558 (P = 0.017 vs. placebo), 86%for sumatriptan ( P < .0.01 vs. placebo) and 25%for placebo. LY293558 and sumatriptan were superi or to placebo (P < .0.01 for all comparisons) on all other measures of improveme nt in pain and migraine associated symptoms. Fifteen percent of patients who too k LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty t hree percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31%of those who received placebo reported AEs (n = 5; four mild, one severe ). The efficacy and safety results of LY293558 in this small migraine proof of c oncept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.
