Schematic diagram of an excitatory synapse and the temporal sequence of synapse formation and maturation. (A) Synapses are specialized junctions between neurons composed of complex membrane and proteins. A synapse can be divided structurally into three parts: a presynaptic axon terminal packed with synaptic vesicles (SV) and release machinery, a synaptic cleft, and a postsynaptic dendritic counterpart filled with neurotransmitter receptors, scaffold proteins and signaling machinery. (B) Synapse formation is initiated by the contact between dendrites and axons, followed by the recruitment of presynaptic and postsynaptic specializations. Increases in synapse size and synaptic strength by accumulation of AMPA receptors at synapses are characteristics of synapse maturation. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; CaMKII, Calcium calmodulin dependent kinase type II; CASK, calcium calmodulin-dependent serine kinase; GKAP, guanylate kinase-associated protein; GRIP, glutamate receptor-interacting protein; InsP3R, inositol triphosphate receptor; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; PSD, postsynaptic density; PSD-95, postsynaptic density protein-95; RIM, Rab3-interacting molecule; SAP, synapse-associated protein; SER, smooth endoplasmic reticulum; SPAR, spine-associated Rap GTPase activating protein; VAMP, vesicle-associated membrane protein; VGCC, voltage-gated calcium channel. (Adapted and modified from ).