The Role of Alternative Splicing of the NMDAR1 Receptor Subunit in Synaptic Plasticity

Abstract

The N-methyl-D-aspartate (NMDA)-type glutamate receptor mediates excitatory transmission in the brain. The NMDA receptor is permeable to Ca++ and is unique among glutamate receptors in that it is blocked by Mg++ in a voltage-dependent manner. In recent years, a great deal of attention has focused on the NMDA receptor owing to its proposed role in brain development, learning and memory, and the neurodegeneration associated with a number of neurological disorders and diseases. NMDA receptor function is also required for the induction of some forms of long-term potentiation (LTP); LTP is thought to underlie memory formation (Bliss and Collingridge, 1993). The NMDA receptor is implicated in neuronal survival and maturation (Balazs et al., 1988; Mattson, 1989), neuronal migration (Komuro and Rakic, 1993), and fine-tuning and stabilization of synaptic connections (Constantine-Paton et al., 1990), including formation of ocular dominance columns (Gu et al., 1989) and development of the olfactory system (Lincoln et al., 1988). Targeted disruption of the NR1 gene in mouse prevents the expression of functional NMDA receptors and causes early death of the mutant mice (Li et al., 1994; Forrest et al., 1994). Overstimulation of the NMDA receptor in response to brain injury triggers a series of steps leading to cell death.