[Molecular mechanism underlying the formation and maintenance of excitatory synapses]

Excitatory synapses in the mammalian brain mainly use glutamate as a transmitter. Excitatory synapses together with inhibitory synapses are essential for the proper functioning of the neural network. Glutamate released from the presynaptic component activates postsynaptic glutamate receptors that are anchored in the postsynaptic density (PSD) and induces subsequent molecular events in the postsynaptic cytoplasm. PSD consists of a network of scaffolding proteins that link membrane receptors and cell adhesion molecules to the cytoplasmic cytoskeletal proteins and signaling molecules. PSD is a dynamic structure that continuously changes its size and molecular composition during development and in response to neuronal activity. Fluorescence-based probes have been developed for PSD scaffolding proteins and are used in studies on the roles of PSD remodeling in the process of neural network development. Continual formation and elimination of PSDs are essential for the process of gradual increase of synaptic density that occurs during the development of the hippocampal neural network in vitro. Rapid turnover of individual PSD scaffolding molecules, which is regulated by filamentous (F)-actin in the postsynaptic cytoplasm, plays an essential role in rapid alterations in PSD sizes and composition. The results of quantitative studies of the molecular content of single PSDs indicate that the local molecular density is sufficiently high to maintain spontaneous interaction between scaffolding molecules. In summary, the available experimental data reveal the roles of PSD scaffolding proteins in dynamic alterations in the postsynaptic structural organization via their domain-specific binding and interaction with the spine actin network. Subtle genetic alterations in PSD proteins may induce neural network dysfunctions that may have some phenotypic relevance in human psychiatric disorders, as suggested in several recent studies.