The subject of this book is the NMDA receptor (NMDAR), a glutamate-gated cation channel that plays myriad roles in the biology and pathophysiology of higher organisms, from fruit flies to humans. The NMDAR is critical for setting up the correct neuronal wiring diagram during brain development, by preventing the elimination of properly functioning synapses [1] and neurons [2]. Starting at birth, NMDARs are involved in generating rhythms, repetitive patterns of burst firing, that organisms use for very basic processes, including breathing and locomotion. The most widely studied aspect of NMDAR function is, however, the role it plays in supporting activity-dependent synaptic plasticity underlying processes of learning and memory. In addition, NMDAR function is important for many higher cognitive brain functions including fear, anxiety, attention, mood, and cognition.

NMDARs belong to the class of ionotropic glutamate receptors (iGluRs) [3], ion channel receptors activated by the excitatory amino acid L-glutamate [4]. They are pharmacologically distinguished from other glutamate receptors (AMPA, kainite, and delta receptors) by their sensitivity to the specific synthetic agonist N-methyl-D-aspartate (NMDA), discovered in the early 1960s by Curtis and Watkins [5,6] before L-glutamate was recognized as a bona fide neurotransmitter in the mammalian nervous system.

Development of radioligand binding assays and specific antagonists during the 1970s led to the idea that several distinct excitatory amino acid receptors existed in the mammalian brain [7], one of which was specifically activated by NMDA. Cloning of the NMDAR NR1 subunit in 1991 [8] and subsequent identification of four genes encoding different NR2 subunits [9] confirmed the existence of separate but related gene families for NMDA and non-NMDA glutamate receptors, and heralded an era of detailed molecular and cellular investigations into the many roles of NMDARs in brain (dys)function.

Important lessons about the various roles of NMDARs in brain function have been learned from recombinant mouse models. The importance of NMDARs for processes involving rhythm generation in the central nervous system is illustrated clearly by the phenotype of the NR1 knockout mouse, which dies hours after birth due to an inability to breathe or suckle [10]. Apparently, NMDARs were employed for rhythm generation very early in evolution. Experiments in Caenorhabditis elegans worms have shown that the NMR-1 subunit, a homologue of the mammalian NR1 subunit, is required for slow NMDA-activated currents in neurons that regulate reversal frequency [11].

Despite the obvious importance of rhythms for the sustenance of life, this aspect of NMDAR function remains poorly studied. Recombinant mice studies have confirmed the importance of NMDAR function for memory formation and consolidation. Overexpression of the immature NR2B subunit, which is highly expressed in developing animals following insertion of an extra copy of the GRIN2B gene in a transgenic mouse, has been reported to enhance learning and memory performance in both adult [12] and aged animals [13]. The role of NMDAR subtypes in specific forms of memory is currently under investigation using mice in which the expression levels of NMDAR genes are altered in specific brain regions and during defined periods [14–17]. Novel functions of NMDARs in memory maintenance are still being discovered. Mice in which NR1 expression is controlled by an inducible, reversible, and region-specific knockout provided evidence for a role of NMDAR reactivation in long-term memory consolidation [18].

This book covers many aspects of the biology of NMDARs: their role in controlling structure and function of synapses and neurons during early development; how overstimulation of NMDARs results in excitotoxicity and contributes to several progressive brain disorders, including Huntington’s disease; the newly discovered and intriguing interactions of NMDARs and dopamine receptors that mediate reward in the central nervous system; the role of NMDARs in alcohol dependence and the promise of NMDAR-based therapeutics for treating alcoholism; how functional expression is controlled at the level of gene transcription by several families of transcription factors; how NMDAR activation regulates local synaptic protein synthesis required for long-term changes in synaptic strength; the modulation of NMDAR function by signaling cascades cumulating in activation of protein kinases and phosphatases; the importance of cellular mechanisms underlying trafficking and targeting of NMDAR protein for many of its physiological functions; how NMDAR-mediated calcium signaling in dendritic spines controls synaptic efficacy and spine morphology; the roles NMDARs play in different temporal phases of memory formation in Drosophila; the extracellular modulation of NMDARs by polyamines, subunit-specific inhibitors, zinc ions, and pH, and the structural bases for their effects; a detailed description of NMDAR pharmacology, structure–activity relationships of agonists and antagonists, and roads to therapeutic drug design; the physiological roles played by NMDARs and their molecular structures; NMDAR activation mechanisms and the therapeutic potential of allosteric modulators; and the novel role of presynaptically localized NMDARs in controlling synaptic plasticity.

An average of 350 papers have appeared annually on the subject of NMDARs since 1994, totaling approximately 5800 research reports by the end of 2007. Although it is impossible to deal with all aspects of NMDAR biology in a single book this size, we have attempted to cover a wide variety of topics and levels of description, from human disease and brain plasticity to gene promoters and X-ray protein structure, with emphasis on cellular and molecular mechanisms. It is hoped that bringing together all these vantage points in a single volume will encourage cross-fertilization among the different disciplines, resulting in a deeper understanding of the hierarchy of processes affected by NMDAR activation and deregulation, from synaptic strengthening to regulating higher cognitive processes. A more complete understanding of all aspects of NMDAR biology may also result in the development of successful therapeutic approaches targeting the NMDAR for the many acute and chronic brain disorders in which the receptor is deregulated.

Antonius M.J. VanDongen