阿尔茨海默病模型中从前额叶皮层到中背侧丘脑的突触信号传递受损，以及激酶抑制剂对此的修复作用

《Journal of Physiology》：Compromised synaptic signal from prefrontal cortex to mediodorsal thalamus in Alzheimer's disease models and its rescue by kinase inhibitors

光遗传学实验证实前额叶皮层（PFC）向中顶核（MD）具有显著神经投射，阿尔茨海默病（AD）模型中突触快速抑郁（STD）异常，tau蛋白过度磷酸化导致轴突运输障碍，SGK1/GSK3β抑制剂可部分恢复Tau模型中的STD但5xFAD模型无效。

　　

摘要

']?>"One of the most important neural circuits controlling cognitive processes is the projection from the prefrontal cortex (PFC) to the thalamus. To determine the strength of PFC projections to different thalamic nuclei, we performed optogenetic experiments by injecting channelrhodopsin-2 (ChR2) into the medial PFC and recording synaptic responses elicited by light stimulation of ChR2-expressing terminals in thalamic neurons. The mediodorsal thalamus (MD) exhibited significantly larger synaptic currents compared to neighboring areas, indicating that the PFC sends strong signals to the MD. To investigate whether the PFC to MD pathway is altered in the early stages of Alzheimer’s disease (AD), we used two mouse models: transgenic mice carrying the human P301S mutation in the microtubule-associated protein tau (Tau), and familial AD mice with five mutations in the APP and PS1 genes (5xFAD). Both models showed a reduced ability of the PFC to induce long-term synaptic potentiation (LTP) in the MD. Optogenetic imaging revealed that Tau mice had significantly reduced ChR2 expression in the axon terminals innervating the MD. Inhibiting kinases such as serum and glucocorticoid-regulated kinase 1 (SGK1) and glycogen synthase kinase-3 beta (GSK3β), which can lead to tau hyperphosphorylation and disrupt microtubule transport in AD, normalized the synaptic responses in Tau mice. However, this effect was not observed in 5xFAD mice. These results suggest that the synaptic connectivity between the PFC and MD is impaired in AD, possibly due to tau kinase-induced disruptions in axonal transport.

关键点

• Optogenetic studies demonstrate a strong connection between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD).
• The ability of the PFC to induce long-term synaptic potentiation (LTP) in the MD is impaired in P301S Tau and 5xFAD mouse models of Alzheimer’s disease (AD).
• Optogenetic imaging shows a reduced PFC-to-MD projection in Tau mice.
• Inhibiting tau kinases SGK1 or GSK3β normalizes the synaptic responses between the PFC and MD in Tau mice, but not in 5xFAD mice.
• These findings indicate that the synaptic transmission from the PFC to the MD is compromised in AD, likely due to tau kinase-induced disruptions in axonal transport.

数据可用性声明

All data are provided upon request.

数据可用性声明

All data are available upon request.