Synaptic transmission and plasticity: molecular mechanisms, biological functions and therapeutic opportunities in neurodegenerative diseases

Synaptic transmission impairment and neuronal loss are hallmarks of neurodegenerative diseases (NDDs). To date, the absence of effective therapies for treating or preventing NDDs underscores the critical need to comprehend the mechanisms underlying synaptic loss and impairment to develop novel interventions. Synaptic transmission is a complex communication process between presynaptic and postsynaptic neurons. Separate postsynaptic receptors activated by a variety of neurotransmitters initiate different downstream signaling cascades that are modulated by receptor-associated auxiliary subunits. Moreover, glia-neuron interactions and various neuropeptides can also modulate diverse synaptic functions. In this review, we first summarize the presynaptic and postsynaptic regulatory mechanisms of synaptic transmission in glutamatergic, GABAergic, cholinergic, and dopaminergic neurons in NDDs. We then emphasize the fundamental role of microglia and astrocytes in maintaining neuronal homeostasis and discuss how glia-neuron cross-talk affects synaptic and neuronal function throughout the pathological processes of NDDs, as well as how aging accelerates synaptic dysfunction in NDDs. We also highlight therapeutic strategies aimed at preserving or restoring synaptic integrity, including approaches that enhance plasticity, fine‑tune neurotransmitter signaling, or target immune pathways. Finally, we evaluate the current state of research for each intervention class and consider the major obstacles and opportunities that lie ahead in developing effective synapse‑directed therapies for NDDs.