Abstract: 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.