Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning.
Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning.
复制标题
DOI：
10.1523/jneurosci.4505-11.2012
复制
发表时间：
2012-11-07
期刊：
影响因子：
--
通讯作者：
Erickson JD
中科院分区：
文献类型：
--
作者：
He H;Mahnke AH;Doyle S;Fan N;Wang CC;Hall BJ;Tang YP;Inglis FM;Chen C;Erickson JD
在出生后发育的关键时期，谷氨酸传递的水平和完整性在锥体神经元树突的细化、突触可塑性和认知中起着重要作用。目前，还不清楚如何兴奋性传输通过两个主要亚型的囊泡谷氨酸转运蛋白（VGLUT 1和VGLUT 2）参与这一过程。为了评估VGLUT 2在锥体神经元成熟中的神经发育作用，我们使用Emx 1-Cre+/+敲入小鼠产生了重组VGLUT 2敲除小鼠并在整个发育过程中灭活VGLUT 2。我们发现，VGLUT 2-皮质边缘电路的缺陷导致减少诱发谷氨酸传输，释放概率，并在海马CA 3-CA 1突触LTD在形成发育期（出生后11-14天）。在成年人中，我们发现在整个CA 1锥体神经元的树突树的跨度，减少LTP和突触标记物spinophilin和VGLUT 1的水平的树突乔木的量显着减少。树突乔木的损失伴随着相应的树突棘的数量减少，这表明突触连接的广泛改变。条件性VGLUT 2敲除小鼠表现出增加的旷场探索活动，但空间学习和记忆受损;内表型与NMDA受体敲除小鼠相似。值得注意的是，学习障碍可以部分恢复选择性增加NMDA受体介导的谷氨酸传输成年小鼠通过长期治疗D-丝氨酸和D-氨基酸氧化酶抑制剂。我们的数据表明，VGLUT 2的表达是关键的成熟的锥体神经元的结构和可塑性的适当发展，并认为这种神经元的缺陷会导致认知功能障碍，如在几个神经发育性精神障碍。
The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation we have generated recombinant VGLUT2 knockout mice and inactivated VGLUT2 throughout development using Emx1-Cre+/+ knockin mice. We show that VGLUT2-deficiency in cortico-limbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11–14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons, reduced LTP and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knockout mice exhibit increased open-field exploratory activity, yet impaired spatial learning and memory; endophenotypes similar to NMDA receptor knockdown mice. Remarkably, the impairment in learning can be partially restored selectively increasing NMDA-receptor mediated glutamate transmission in adult mice by prolonged treatment with D-serine and a D-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders.