A new model of polarized initiation of neuronal varicosities induced by mechanical stress. (A) Diagram of signaling molecules on both sides of axonal membrane under control condition. (B) Mechanical stress induces a signaling cascade across the axonal membrane to induce axonal varicosity formation. (C–E) A new model diagram of sequential axonal and dendritic swelling under pathological mechanical stress. (C) Dendrites, dendritic spines, and axons under normal conditions. (D) Under mechanical stress, axonal varicosities start to form while dendrites and dendritic spines remain unchanged. (E) Under prolonged or pathological mechanical stresses, axonal varicosities become irreversible and are eventually broken to release the neurotransmitter glutamate, which can overstimulate its receptors on dendrites to induce swelling and hence neuronal death. (F) Prolonged stimulation of Glu (particularly NMDA) receptors causes swelling in dendrites but not in axons.