The NMDA receptor is an ionotropic receptor comprising of an extracellular amino terminal domain, 3 transmembrane domains, a re-entrant loop, intracellular carboxyl domain, and a ligand binding domain. Specific signalling molecules/phosphorylation sites involved in trafficking of the NMDA receptor are thought to influence its surface expression. Schizophrenia is a severe mental disorder characterised by positive, negative and cognitive symptoms, where NMDA receptor hypofunction has been implemented in the pathophysiology of this disease. The activation of the NMDA receptor can be influenced both directly and indirectly. Negative modulation of the NMDA receptor includes glycine transporter 1, endogenous agonists such as kynurenic acid and many genes including neuregulin 1 gene. Positive modulation involves direct and indirect glycine modulatory site agonists, where experimental treatment of NMDA receptor hypofunction has been most successful by glycine modulatory site agonists. Many brain regions seem to be affected in schizophrenia in particular the prefrontal cortex.
Schizophrenia is a chronic disorder characterised by positive, negative, and cognitive symptoms. Schizophrenic subjects with positive symptoms often show signs of hallucinations, and delusions, whilst those with negative symptoms show lack of motivation and social withdrawal. Cognitive symptoms often comprise of disrupted working memory and symptoms associated with cortical processing. The positive symptoms are thought to be as a result of dopamine hyperactivity whereas the negative/cognitive symptoms have been associated with glutamate hypoactivity.
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Traditionally the dopamine theory dominated research. Over the years it has become evident namely dopamine, γ-aminobutyric acid, and serotonin play a role in schizophrenia. Although these neurotransmitters dysfunction seem to exert some effects on the brain, they only account for less than 50% of the neurons present within the human brain, which suggests their significance is not as great as the NMDA receptors (Javitt 2006).
However, since the glutamate hypothesis of schizophrenia came into existence, particularly over the last decade or so, much knowledge has been acquired about the role of the glutamatergic system in the pathophysiology of schizophrenia to suggest dopamine hyperfunction is not the only mechanism, which produces symptoms of schizophrenia. Since the glutamate neurotransmitter accounts for more than 60% of neurons in the human brain, and virtually all synapses contain glutamate receptors, then it would seem very likely glutamate plays a crucial role in schizophrenia.
There are 3 major families of the glutamate receptors, AMPA, NMDA and Kainate, each named after their selective agonists. In the case of schizophrenia an extensive amount of evidence has suggested hypofunction of the NMDA family of receptors to be the main receptor type mediating the negative and cognitive symptoms.
This review will focus on the basic glutamate receptor (NMDAR): structure and function, agonist binding to the receptor, modulation of the receptor, as well as how the components of signalling/trafficking are involved in NMDA surface expression, and how all these components of the NMDAR are involved in hypofunction ultimately leading to symptoms of schizophrenia. Consequently particular brain areas affected as well as current methods of enhancing the NMDAR function will be considered.
Focus on NMDA glutamate receptor structure
L-glutamate is the potent neurotransmitter in the brain accounting for the slow and fast excitatory post-synaptic potentials. This major excitatory amino acid neurotransmitter is known to activate both the ionotropic and metabotropic glutamate receptors. As mentioned above the three distinct ionotropic receptors are N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate, each characterised by their preferred agonists (Meldrum 2000).
NMDA receptors are unique in that they require both glutamate and glycine for activation, whilst the non NMDA receptors AMPA and Kainate, are activated solely by glutamate (Furukawa et al 2005). This major difference arises as a result of the NMDA receptor genes NR1, NR2 and NR3, which encode for a particular receptor subunit (Mayer and Armstrong 2003, Kew and Kemp 2005).
Individual subunit composition
Each of the individual receptor subunits of the eukaryotic NMDA receptor (NMDAR) contain an extracellular amino terminal domain, with 3 transmembrane domains, a re-entrant loop (that does not cross the membrane), intracellular carboxyl domain, and a ligand binding domain (figure1) (Dingledine et al 1999, Mayer and Armstrong 2003, Kew and Kemp 2005). These components are explored in more detail below.
NMDA receptor subunits and genes
To understand the NMDA receptor structure and assembly, one must first consider the individual subunits encoded by the 7 separate genes. As mentioned above there are 3 possible subunit variants of the NMDA receptor encoded by the NR1, NR2, and NR3 genes giving rise to a total of 7 NMDA receptor family subunits (table1) (Mayer and Armstrong 2003, Kew and Kemp 2005, Stephenson 2006).
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In addition to table 1, it should also be noted the NR1 gene undergoes alternative splicing at exons 5, 21, and 22 (Chen and Roche 2007) to yield 8 functional splice variants of the NR1 subunits, which are NR1-1a, NR1-1b ranging to NR1-2a, NR1-2b, NR1-3a, NR1-3b, NR1-4a and NR1-4b (Mcbain and Mayer 1994, Stephenson 2006, Paoletti and Neyton 2007).
The NR2 subunits show approximately 21% homology with NR1 and around 38-53% amino acid sequence homology with themselves. On the other hand, the NR3 has been estimated to show around 27% with NR1 and NR2 subunits, whilst displaying around 50% amino acid sequence identity amongst themselves (Kew and Kemp 2005), showing these subunits as well sharing similarity, they are also significantly different to each other.
NMDA Receptor Subunits
Preferred Subunit Agonist
Table 1 - The possible subunits of the NMDA receptor family is summarised followed by the agonists each subunit selectively binds to.
NMDA receptor quaternary structure
Having considered the possible subunits of the NMDA receptor (NMDAR), the actual receptor composition and quaternary structure can be explained. It is now well known the native receptors of the glutamate receptors all assemble as a tetramer based on the biochemical, electrophysiological studies (Rosenmund et al 1998, Kuusinen et al 1999, Ayalon and Stern-Bach 2001). The pair subunits are thought to be organised as a 'dimer of dimers' mediated by the ATD and the ligand binding domain (figure2) (Madden 2002, Mayer and Armstrong 2003, Tichelaar et al 2004). Much study on the AMPA receptors has also supported the formation of a 'dimer of dimers' through the ATD and the ligand binding domain (LBD), which is also present amongst the NMDAR's (Ayalon and Stern-Bach 2001).