During development, critical periods of synaptic plasticity facilitate the reordering and refinement of neural connections, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. The L4–L2/3 synapses in the somatosensory cortex (S1) exhibit a presynaptic form of spike timing-dependent long-term depression (t-LTD) that probably fulfills a role in synaptic refinement. This t-LTD persists until the fourth postnatal week in mice, disappearing thereafter. When we investigated the mechanisms underlying this maturation-related loss of t-LTD in either sex mouse slices, we found that it could be completely recovered by antagonizing adenosine type 1 receptors. By contrast, an agonist of A₁R impeded the induction of t-LTD at P13–27. Furthermore, we found that the adenosine that mediated the loss of t-LTD at the end of the fourth week of development is most probably supplied by astrocytes. At more mature stages (P38–60), we found that the protocol used to induce t-LTD provokes t-LTP. We characterized the mechanisms underlying the induction of this form of LTP, and we found it to be expressed presynaptically, as witnessed by paired-pulse and coefficient of variation analysis. In addition, this form of presynaptic t-LTP requires the activation of NMDARs and mGlu1Rs, and the entry of Ca²⁺ into the postsynaptic neuron through L-type voltage-dependent Ca²⁺ channels. Nitric oxide is also required for t-LTP as a messenger in the postsynaptic neuron as are the adenosine and glutamate that are released in association with astrocyte signaling. These results provide direct evidence of the mechanisms that close the window of plasticity associated with t-LTD and that drive the switch in synaptic transmission from t-LTD to t-LTP at L4–L2/3 synapses, in which astrocytes play a central role.

SIGNIFICANCE STATEMENT During development, critical periods of plasticity facilitate the reordering and refining of neural connections, allowing correct adult physiology to be established. The L4–L2/3 synapses in the somatosensory cortex exhibit a presynaptic form plasticity (LTD) that probably fulfills a role in synaptic refinement. It is present until the fourth postnatal week in mice, disappearing thereafter. The mechanisms that are responsible for this loss of plasticity are not clear. We describe here these mechanisms and those involved in the switch from LTD to LTP observed as the brain matures. Defining these events responsible for closing (and opening) plasticity windows may be important for brain repair, sensorial recovery, the treatment of neurodevelopmental disorders, and for educational policy.

在发育过程中，突触可塑性的关键时期促进神经连接的重新排序和细化，从而建立负责正确成人生理学的明确突触回路。体感皮层 (S1) 中的 L4–L2/3 突触表现出突触前形式的尖峰时序依赖性长期抑制 (t-LTD)，这可能在突触细化中发挥作用。这种 t-LTD 在小鼠中持续到出生后第四周，此后消失。当我们研究两性小鼠切片中这种与成熟相关的 t-LTD 缺失的机制时，我们发现可以通过拮抗 1 型腺苷受体来完全恢复它。相比之下，A ₁ R 激动剂阻碍了 P13-27 t-LTD 的诱导。此外，我们发现在发育第四周结束时介导 t-LTD 损失的腺苷很可能是由星形胶质细胞提供的。在更成熟的阶段 (P38-60)，我们发现用于诱导 t-LTD 的方案会引发 t-LTP。我们描述了诱导这种 LTP 形式的机制，并发现它在突触前表达，正如配对脉冲和变异系数分析所证明的那样。此外，这种形式的突触前t-LTP需要NMDAR和mGlu1R的激活，以及Ca ²⁺通过L型电压依赖性Ca ²⁺通道进入突触后神经元。作为突触后神经元中的信使，一氧化氮也是 t-LTP 所必需的，与星形胶质细胞信号传导相关的腺苷和谷氨酸也是如此。 这些结果提供了关闭与 t-LTD 相关的可塑性窗口并驱动 L4-L2/3 突触处突触传递从 t-LTD 到 t-LTP 转换的机制的直接证据，其中星形胶质细胞发挥着核心作用。

意义陈述在发育过程中，可塑性的关键时期促进神经连接的重新排序和完善，从而建立正确的成人生理学。体感皮层中的 L4-L2/3 突触表现出突触前形式可塑性 (LTD)，可能在突触细化中发挥作用。它在小鼠中一直存在到出生后第四周，此后消失。导致可塑性丧失的机制尚不清楚。我们在这里描述这些机制以及随着大脑成熟观察到的从 LTD 到 LTP 转换所涉及的机制。定义这些负责关闭（和打开）可塑性窗口的事件可能对于大脑修复、感觉恢复、神经发育障碍的治疗和教育政策很重要。