Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer’s disease

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease (AD). High-frequency stimulation (HFS)-induced long-term potentiation (LTP) has been widely used to study synaptic plasticity, with impaired LTP found to be associated with AD. However, the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated. Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear. Herein, we induced LTP in the hippocampal CA1 region of wild-type (WT) and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region. We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes (DEGs) in mice with normal LTP, and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP. We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction. Among them, we found that the expression of Pygm, which catabolizes glycogen, was also decreased in AD patients. We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice, while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice. Moreover, we showed that PYGM directly regulated energy generation in neurons. Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function, but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.突触功能障碍是阿尔茨海默病（Alzheimer’s disease, AD）的一个重要病理标志和影响因素。高频刺激（High frequency stimulation, HFS）诱导的长时程增强（Long-term potentiation, LTP）已经被广泛用于研究突触可塑性，并且LTP受损与AD相关。然而，突触可塑性的确切分子机制还没有被完全阐明，调控突触可塑性的基因是否在AD中发生改变并导致疾病的发生也有待探究。在此，我们通过在CA3区提供HFS诱导野生型（Wild-type, WT）和AD模型小鼠的海马CA1区的LTP，然后研究CA1区的转录组变化。通过筛选LTP表现正常的小鼠中HFS诱导的差异表达基因（DEGs），我们确定了89个可能参与正常突触可塑性的基因；通过比较LTP表现正常小鼠和LTP受损的AD小鼠中HFS诱导的DEGs的变化差异，确定了43个可能导致AD突触功能障碍的基因。我们通过筛选那些在没有HFS诱导的病理阶段的AD小鼠中表达已经发生改变的基因，进一步将这43个基因的范围缩小到14个。其中，我们发现分解糖原的PYGM的表达在AD患者中也有所下降。我们进一步证明，PYGM在神经元中的下调损害了WT小鼠的突触可塑性和认知能力，而PYGM在神经元中的过表达则缓解了AD小鼠的突触功能障碍和认知缺陷。此外，我们发现PYGM直接调节神经元的能量生成。我们的研究不仅表明PYGM介导的神经元能量产生在突触功能中起着重要作用，而且还提供了一种新的、基于LTP的策略来系统地识别生理和病理条件下调节突触可塑性的基因。.