Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
Institute of Experimental Epileptology and Cognition Research, Medical Faculty, University of Bonn, Bonn, Germany.
Nat Commun. 2022 Dec 24;13(1):7932. doi: 10.1038/s41467-022-35620-8.
Dendrites of hippocampal CA1 pyramidal cells amplify clustered glutamatergic input by activation of voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). NMDAR activity depends on the presence of NMDAR co-agonists such as D-serine, but how co-agonists influence dendritic integration is not well understood. Using combinations of whole-cell patch clamp, iontophoretic glutamate application, two-photon excitation fluorescence microscopy and glutamate uncaging in acute rat and mouse brain slices we found that exogenous D-serine reduced the threshold of dendritic spikes and increased their amplitude. Triggering an astrocytic mechanism controlling endogenous D-serine supply via endocannabinoid receptors (CBRs) also increased dendritic spiking. Unexpectedly, this pathway was activated by pyramidal cell activity primarily in the theta range, which required HCN channels and astrocytic CB1Rs. Therefore, astrocytes close a positive and frequency-dependent feedback loop between pyramidal cell activity and their integration of dendritic input. Its disruption in mice led to an impairment of spatial memory, which demonstrated its behavioral relevance.
海马 CA1 锥体神经元的树突通过电压门控钠离子通道和 N-甲基-D-天冬氨酸受体 (NMDAR) 的激活来放大簇状谷氨酸能输入。NMDAR 活性取决于 NMDAR 共激动剂（如 D-丝氨酸）的存在，但共激动剂如何影响树突整合尚不清楚。我们使用全细胞膜片钳、离子电泳谷氨酸应用、双光子激发荧光显微镜和谷氨酸光解在急性大鼠和小鼠脑片中发现，外源性 D-丝氨酸降低了树突棘的阈值并增加了其幅度。通过内源性大麻素受体 (CBR) 触发控制内源性 D-丝氨酸供应的星形胶质细胞机制也增加了树突棘放电。出乎意料的是，该途径主要通过 theta 范围的锥体细胞活动激活，这需要 HCN 通道和星形胶质细胞 CB1R。因此，星形胶质细胞在锥体细胞活动与其树突输入整合之间形成正的、频率依赖性的反馈回路。在小鼠中破坏该回路导致空间记忆受损，证明了其行为相关性。
