Glutamic acid is an important neurotransmitter in the central nervous system. It acts as the main agonist of NMDA receptors located on the postsynaptic membrane in many areas of the brain.
The NMDA is a ionotropic receptor that is able to function as an ion channel after activation of the specific ligand and/or other molecules. The ions Na+ and Ca2+ are inside the neuron while K+ flows to its exterior.
It consists of several subunits, the innermost of which constitutes the wall of the ion channel. It takes its name from the N-Methyl-D-Aspartate, a molecule that positively regulates once linked to its specific site.
The subunit of this receptor has been identified and cloned: NR1, NR2A-D and NR3A-B. The NR1 subunit is found in all brain regions, while the subunits NR2A-D are present primarily in the neocortex, hippocampus, and cerebellum.
The NR1 subunit is always present in the NMDA receptors of every type, and includes asparagine sites giving high ability to bind magnesium ions and high permeability to calcium, which are indispensable characteristics to depolarization. In order to allow the entry and binding of calcium ions to the NMDA receptor another substance must be added to the allosteric site in addition to the principal agonist. In most cases this substance is glycine.
The entry of calcium activates phospholipase A2, the nitric oxide synthase and ornithine decarboxylase, which in turn determines the block of magnesium, an enhanced presynaptic release and uptake of glutamate and the influx of calcium ions.
In a large-scale study conducted by the Consortium on the Genetics of Schizophrenia, the organization noted that NMDA receptor NR1, NR2A, and NR2B subunits polymorphisms are often associated with the diagnosis of schizophrenia. Through further research a relevant association with NMDA subunits alteration has been identified also for autism spectrum disorders: a postmortem study revealed a differential splicing of NR1 and other gene association analyses showed a reduction of NMDA-mediated neurotransmission. In addition, recent work on transgenic mice (for the SHANK3, NLGN1, NRXN1, FMRP1, MeCP2, DISC1, RELN genes) and rodents exposed in utero, respectively considered models of autism and autism risk, showed a reduced activity of the NMDA receptor signaling.
Harmful mutations of NR1, NR2A, and NR2B have been identified through large-scale studies, also in people with intellectual disabilities.
Considering all of the data, these results indicate that a dysfunction of NMDA receptor signaling may represent a molecular substrate common to several neuropsychiatric disorders of development.
REFERENCES
- Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010; 42: 1021-1026.
- Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 2011; 88: 306-316.
-Saunders JA, Gandal MJ, Roberts TP, Siegel SJ. NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders. Behav Brain Res. 2012 Jul 5;234(2):233-237. [Epub ahead of print]