Synaptic fatigue, also known as synaptic depression, refers to the temporary decrease in synaptic efficiency following prolonged or repetitive stimulation of a synapse. It occurs when the presynaptic neuron depletes its supply of neurotransmitters faster than it can replenish them. As a result, fewer neurotransmitters are released into the synaptic cleft, reducing the strength of the signal transmitted to the postsynaptic neuron.

This phenomenon acts as a protective mechanism, preventing overstimulation of neurons and allowing the synapse time to recover. Synaptic fatigue is commonly observed during high-frequency stimulation and can influence neural plasticity, learning, and memory.