Graduate Program in Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2012 Sep 19;32(38):13100-10. doi: 10.1523/JNEUROSCI.2604-12.2012.
Astrocytes contribute to many neuronal functions, including synaptogenesis, but their role in the development of synaptic plasticity remains unclear. Presynaptic muting of hippocampal glutamatergic terminals defends against excitotoxicity. Here we studied the role of astrocytes in the development of presynaptic muting at glutamatergic synapses in rat hippocampal neurons. We found that astrocytes were critical for the development of depolarization-dependent and G(i/o)-dependent presynaptic muting. The ability of cAMP analogues to modulate presynaptic function was also impaired by astrocyte deficiency. Although astrocyte deprivation resulted in postsynaptic glutamate receptor deficits, this effect appeared independent of astrocytes' role in presynaptic muting. Muting was restored with chronic, but not acute, treatment with astrocyte-conditioned medium, indicating that a soluble factor is permissive for muting. Astrocyte-derived thrombospondins (TSPs) are likely responsible because TSP1 mimicked the effect of conditioned medium, and gabapentin, a high-affinity antagonist of TSP binding to the α2δ-1 calcium channel subunit, mimicked astrocyte deprivation. We found evidence that protein kinase A activity is abnormal in astrocyte-deprived neurons but restored by TSP1, so protein kinase A dysfunction may provide a mechanism by which muting is disrupted during astrocyte deficiency. In summary our results suggest an important role for astrocyte-derived TSPs, acting through α2δ-1, in maturation of a potentially important form of presynaptic plasticity.
星形胶质细胞参与许多神经元功能，包括突触发生，但它们在突触可塑性发展中的作用尚不清楚。海马谷氨酸能末梢的突触前沉默可防止兴奋毒性。在这里，我们研究了星形胶质细胞在大鼠海马神经元中谷氨酸能突触的突触前沉默发展中的作用。我们发现星形胶质细胞对于去极化依赖性和 G(i/o)-依赖性突触前沉默的发展是至关重要的。环磷酸腺苷类似物调节突触前功能的能力也因星形胶质细胞缺乏而受损。尽管星形胶质细胞剥夺导致突触后谷氨酸受体缺陷，但这种效应似乎与星形胶质细胞在突触前沉默中的作用无关。慢性而非急性星形胶质细胞条件培养基处理可恢复沉默，表明可溶性因子可促进沉默。星形胶质细胞衍生的血栓素 (TSPs) 可能是原因，因为 TSP1 模拟了条件培养基的作用，而加巴喷丁，一种高亲和力的 TSP 与α2δ-1 钙通道亚基结合的拮抗剂，模拟了星形胶质细胞剥夺。我们发现证据表明，蛋白激酶 A 活性在星形胶质细胞剥夺的神经元中异常，但 TSP1 可恢复其活性，因此蛋白激酶 A 功能障碍可能为星形胶质细胞缺乏时沉默中断提供了一种机制。总之，我们的结果表明，星形胶质细胞衍生的 TSPs 通过α2δ-1 发挥作用，在一种潜在重要的突触前可塑性成熟中起着重要作用。
