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Does conventional anti-bipolar and antidepressant drug therapy reduce NMDA-mediated neuronal excitation by downregulating astrocytic GluK2 function?

机译:传统的抗双极抗抑郁药物疗法是否会通过下调星形细胞GluK2功能来减少NMDA介导的神经元兴奋?

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摘要

Chronic treatment with anti-bipolar drugs (lithium, carbamazepine, and valproic acid) down-regulates mRNA and protein expression of kainate receptor GluK2 in mouse brain and cultured astrocytes. It also abolishes glutamate-mediated, Ca 2+-dependent ERK 1/2 phosphorylation in the astrocytes. Chronic treatment with the SSRI fluoxetine enhances astrocytic GluK2 expression, but increases mRNA editing, abolishing glutamate-mediated ERK 1/2 phosphorylation and [Ca 2+] i increase, which are shown to be GluK2-mediated. Neither drug group affects Glu4/Glu5 expression necessary for GluK2's ionotropic effect. Consistent with a metabotropic effect, the PKC inhibitor GF 109203X and the IP 3 inhibitor xestospongin C abolish glutamate stimulation in cultured astrocytes. In CA1/CA3 pyramidal cells in hippocampal slices, activation of extrasynaptic GluK2 receptors, presumably including astrocytic, metabotropic GluK2 receptors, causes long-lasting inhibition of slow neuronal afterhyperpolarization mediated by Ca 2+-dependent K + flux. This may be secondary to the induced astrocytic [Ca 2+] i increase, causing release of 'gliotransmitter' glutamate. Neuronal NMDA receptors respond to astrocytic glutamate release with enhancement of excitatory glutamatergic activity. Since reduction of NMDA receptor activity is known to have antidepressant effect in bipolar depression and major depression, these observations suggest that the inactivation of astrocytic GluK2 activity by antidepressant/anti-bipolar therapy ameliorates depression by inhibiting astrocytic glutamate release. A resultant strengthening of neuronal afterhyperpolarization may cause reduced NMDA-mediated activity.
机译:长期使用抗双极性药物(锂,卡马西平和丙戊酸)下调小鼠脑和培养的星形胶质细胞中的海藻酸盐受体GluK2的mRNA和蛋白表达。它还消除了星形胶质细胞中谷氨酸介导的Ca 2+依赖性ERK 1/2磷酸化。用SSRI氟西汀进行的慢性治疗可增强星形细胞GluK2的表达,但会增加mRNA的编辑,从而消除谷氨酸介导的ERK 1/2磷酸化和[Ca 2+] i的增加,这证明是由GluK2介导的。两种药物都不会影响GluK2的离子作用所必需的Glu4 / Glu5表达。与促代谢作用一致,PKC抑制剂GF 109203X和IP 3抑制剂xestospongin C消除了培养的星形胶质细胞中的谷氨酸刺激。在海马切片的CA1 / CA3锥体细胞中,突触外GluK2受体(可能包括星形细胞,代谢型GluK2受体)的激活会长期抑制由Ca 2+依赖的K +通量介导的慢神经元超极化。这可能是继发的星形胶质细胞[Ca 2+] i增加,继而导致释放“神经递质”谷氨酸的原因。神经元NMDA受体通过增强兴奋性谷氨酸能活性来响应星形细胞谷氨酸释放。由于已知NMDA受体活性的降低在双相抑郁和重度抑郁中具有抗抑郁作用,因此这些观察结果表明,抗抑郁/抗双极性疗法对星形胶质细胞GluK2活性的灭活可通过抑制星形胶质谷氨酸的释放来改善抑郁症。神经元超极化后的增强可能导致NMDA介导的活性降低。

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