A Myosin Va mutant mouse with disruptions in glutamate synaptic development and mature plasticity in visual cortex.
A Myosin Va mutant mouse with disruptions in glutamate synaptic development and mature plasticity in visual cortex.
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DOI：
10.1523/jneurosci.4585-12.2013
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发表时间：
2013-05-08
期刊：
影响因子：
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通讯作者：
Constantine-Paton M
中科院分区：
文献类型：
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作者：
Yoshii A;Zhao JP;Pandian S;van Zundert B;Constantine-Paton M
肌球蛋白Va(myosinVa，MyoVa)介导以F-肌动蛋白为基础的囊泡向质膜的运输，存在于神经元突触后密度(PSD)，但MyoVa在突触发育和功能中的作用尚不清楚。在这里，在使用显性负性MyoVa神经学突变小鼠的研究中，我们发现MyoVa在PSD-95和其他关键PSD分子的活性依赖性递送到突触以及在中枢神经系统神经元树突中AMPA型谷氨酸受体(AMPAR)的内吞中发挥重要作用。已知MyoVa携带一个包含成熟PSD、PSD-95、SAPAP1/GKAP、Shank和Hmer的主要支架蛋白的复合体，到达树突突触。在Flailer中，神经元显示PSD-95、Stargazin、Dynamin3、AMPA谷氨酸受体(AMPAR)的树突干定位异常，以及脊椎形态异常。Flailer神经元也具有异常高的AMPAR微小电流频率和自发AMPAR电流，这些电流比WT更频繁和更大，而含有NMDAR的突触数量保持正常。AMPAR的异常与我们在皮质翻转神经元中发现的长期抑郁的严重发育调节中断一致。因此，MyoVa在将成熟的谷氨酸突触定位到脊椎和组织突触以实现正常功能方面都起着至关重要的作用。出于这个原因，Flailer小鼠在进一步剖析MyoVa在正常突触和电路完善中的作用以及在神经和神经精神疾病的研究中将是有价值的，因为在这些疾病中，经常可以观察到正常谷氨酸突触的破坏。
MyosinVa (MyoVa) mediates F-actin-based vesicular transport toward the plasma membrane and is found at neuronal postsynaptic densities (PSDs), but the role of MyoVa in synaptic development and function is largely unknown. Here, in studies using the dominant negative MyoVa neurological mutant mouse Flailer, we find that MyoVa plays an essential role in activity-dependent delivery of PSD-95 and other critical PSD molecules to synapses and in endocytosis of AMPA-type glutamate receptors (AMPAR) in the dendrites of CNS neurons. MyoVa is known to carry a complex containing the major scaffolding proteins of the mature PSD, PSD-95, SAPAP1/GKAP, Shank and Homer, to dendritic spine synapses. In Flailer, neurons show abnormal dendritic shaft localization of PSD-95, stargazin, dynamin3, AMPA glutamate receptors (AMPARs) and abnormal spine morphology. Flailer neurons also have abnormally high AMPAR miniature current frequencies and spontaneous AMPAR currents that are more frequent and larger than in WT while numbers of NMDAR containing synapses remain normal. The AMPAR abnormalities are consistent with a severely disrupted developmental regulation of long-term depression that we find in cortical Flailer neurons. Thus MyoVa plays a fundamentally important role both in localizing mature glutamate synapses to spines and in organizing the synapse for normal function. For this reason Flailer mice will be valuable in further dissecting the role of MyoVa in normal synaptic and circuit refinement and also in studies of neurological and neuropsychiatric diseases where disruptions of normal glutamate synapses are frequently observed.