Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.