Van Horn Marion R, Strasser Arielle, Miraucourt Lois S, Pollegioni Loredano, Ruthazer Edward S
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, 21100 Varese, Italy, and.
J Neurosci. 2017 Jun 28;37(26):6277-6288. doi: 10.1523/JNEUROSCI.3158-16.2017. Epub 2017 May 26.
The NMDAR is thought to play a key role in the refinement of connectivity in developing neural circuits. Pharmacological blockade or genetic loss-of-function manipulations that prevent NMDAR function during development result in the disorganization of topographic axonal projections. However, because NMDARs contribute to overall glutamatergic neurotransmission, such loss-of-function experiments fail to adequately distinguish between the roles played by NMDARs and neural activity in general. The gliotransmitter d-serine is a coagonist of the NMDAR that is required for NMDAR channel opening, but which cannot mediate neurotransmission on its own. Here we demonstrate that acute administration of d-serine has no immediate effect on glutamate release or AMPA-mediated neurotransmission. We show that endogenous d-serine is normally present below saturating levels in the developing visual system of the tadpole. Using an amperometric enzymatic biosensor, we demonstrate that glutamatergic activation elevates ambient endogenous d-serine levels in the optic tectum. Chronically elevating levels of d-serine promoted synaptic maturation and resulted in the hyperstabilization of developing axon branches in the tadpole visual system. Conversely, treatment with an enzyme that degrades endogenous d-serine resulted in impaired synaptic maturation. Despite the reduction in axon arbor complexity seen in d-serine-treated animals, tectal neuron visual receptive fields were expanded, suggesting a failure to prune divergent retinal inputs. Together, these findings positively implicate NMDAR-mediated neurotransmission in developmental synapse maturation and the stabilization of axonal inputs and reveal a potential role for d-serine as an endogenous modulator of circuit refinement. Activation of NMDARs is critical for the activity-dependent development and maintenance of highly organized topographic maps. d-Serine, a coagonist of the NMDAR, plays a significant role in modulating NMDAR-mediated synaptic transmission and plasticity in many brain areas. However, it remains unknown whether d-serine participates in the establishment of precise neuronal connections during development. Using an model, we show that glutamate receptor activation can evoke endogenous d-serine release, which promotes glutamatergic synapse maturation and stabilizes axonal structural and functional inputs. These results reveal a pivotal modulatory role for d-serine in neurodevelopment.
N-甲基-D-天冬氨酸受体（NMDAR）被认为在发育中的神经回路连接精细化过程中起关键作用。在发育过程中，药理学阻断或基因功能丧失操作若阻止NMDAR发挥功能，会导致轴突拓扑投射紊乱。然而，由于NMDAR参与整体谷氨酸能神经传递，此类功能丧失实验无法充分区分NMDAR和一般神经活动所起的作用。神经胶质递质D-丝氨酸是NMDAR的协同激动剂，是NMDAR通道开放所必需的，但它自身无法介导神经传递。在此，我们证明急性给予D-丝氨酸对谷氨酸释放或AMPA介导的神经传递没有即时影响。我们发现，在蝌蚪发育中的视觉系统中，内源性D-丝氨酸通常以低于饱和水平的浓度存在。使用安培型酶生物传感器，我们证明谷氨酸能激活会提高视顶盖中环境内源性D-丝氨酸水平。长期提高D-丝氨酸水平可促进突触成熟，并导致蝌蚪视觉系统中发育中的轴突分支超稳定。相反，用降解内源性D-丝氨酸的酶进行处理会导致突触成熟受损。尽管在D-丝氨酸处理的动物中观察到轴突分支复杂性降低，但顶盖神经元的视觉感受野却扩大了，这表明未能修剪发散的视网膜输入。总之，这些发现明确表明NMDAR介导的神经传递在发育性突触成熟和轴突输入稳定中起作用，并揭示了D-丝氨酸作为回路精细化内源性调节剂的潜在作用。NMDAR的激活对于高度组织化拓扑图谱的活动依赖性发育和维持至关重要。D-丝氨酸作为NMDAR的协同激动剂，在调节许多脑区中NMDAR介导的突触传递和可塑性方面发挥重要作用。然而，D-丝氨酸在发育过程中是否参与精确神经元连接的建立仍不清楚。使用一个模型，我们表明谷氨酸受体激活可引发内源性D-丝氨酸释放，这促进谷氨酸能突触成熟并稳定轴突的结构和功能输入。这些结果揭示了D-丝氨酸在神经发育中的关键调节作用。
