Developmental modification of synaptic NMDAR composition and maturation of glutamatergic synapses: matching postsynaptic slots with receptor pegs.

The numbers and types of ionotropic glutamate receptors at most vertebrate central excitatory synapses are altered as a function of changes in input activity patterns that occur during postnatal development. Activity-dependent developmental alterations in glutamate receptors underlie lasting changes in synaptic efficacy (plasticity) and metaplasticity (the plasticity of synaptic plasticity), which are critical elements of normal brain maturation. Understanding the specific involvement of glutamate receptors in synaptic development and function is made multiplicatively complex by the existence of a large number of glutamate receptor subunits, numerous subunit-specific amino acid sequences that regulate receptor function, and subunit-specific synaptic insertion restrictions imposed by associated anchoring proteins. Many receptor properties are altered when subunits are switched, so it is unclear which individual receptor property or properties underlie changes in synaptic function and plasticity during postnatal development. As a result, a more detailed understanding of the factors that regulate synaptic and cognitive development will involve mutations in glutamate receptor subunits that separate individual receptor properties and permit synaptic insertion at both immature and mature synapses in genetically modified organisms. This position paper focuses on structural modifications in N-methyl-d-aspartate receptors (NMDARs) that occur during postnatal forebrain development and attempts to provide a method for pursuing a more complete understanding of the functional ramifications of developmental alterations in NMDAR subunit composition.