1 November 2012. The NMDA receptor is one of the most highly implicated receptors in schizophrenia development and pathophysiology. Despite this, post mortem studies examining the NMDA receptor have been inconclusive, with various reports showing increases, decreases and no change across the various NMDA receptor subunits.
Recently, however, a collaborative effort across the Schizophrenia Research Institute’s laboratories, led by the Weickert group, have corroborated that the NMDA receptor is altered in schizophrenia.
Using techniques across molecular neuroscience and psychological disciplines, leading schizophrenia researchers Cyndi and Tom Weickert have led a study to analyse alterations in NMDA receptor subunits at the genetic, mRNA, and protein levels within the dorsolateral prefrontal cortex (a brain region with cognitive functions) of post-mortem schizophrenia brains, as well as correlating this with cognitive function in antemortem patients with schizophrenia.
In the largest post-mortem cohort to date, this comprehensive study has reported alterations across the various levels of transcription in a number of NMDA receptor subunits, suggesting that the NMDA receptor may, after all, be altered in schizophrenia sufferers.
How did they test it?
To get a true understanding of how the NMDA receptor might be altered in the schizophrenia brain, Weickert and team studied the NMDA receptor subunits at various translation levels in the dorsolateral prefrontal cortex of schizophrenia subjects and matched controls. mRNA transcripts were measured for NR1, NR2A, NR2B, NR2C and NR3A subunits of the NMDA receptor, and this was supplemented with NR1 protein levels.
The NMDA receptor itself is complex in nature, consisting of two obligatory NR1 subunits accompanied by a combination of two NR2 (NR2A-D) or NR3 subunits (NR3A and B). Alterations in the NR1 subunit may be thought as the most detrimental, as the NMDA receptor cannot survive without it. In light of this, the most exciting result was that both NR1 mRNA and protein were reduced in the dorsolateral prefrontal cortex of subjects with schizophrenia, strongly suggesting that NMDA receptor levels are reduced in schizophrenia pathophysiology.
An additional finding of decreased NR2C mRNA suggests that there may be alterations in receptor composition. As NMDA receptor composition is indicative of function, this could have implications for NMDA receptor-related signalling. However, it should be noted that altered mRNA levels do not necessarily translate to alterations of protein (see Greenbaum et al., 2003). Since NR2C protein was not measured in the present study, this remains to be speculation.
A handful of NMDA receptor SNPs that had previously been associated with schizophrenia were also analysed to complete the picture. These SNPs were then correlated with antemortem measures of cognitive function. The minor C allele of the NR2B gene SNP rs1805502 was associated with lower reasoning ability in patients with schizophrenia, and this also correlated with reduced levels of NR1 mRNA and protein in the dorsolateral prefrontal cortex. This signifies an intricate relationship between NMDA receptor subunits, across various levels of protein translation, and suggests that perhaps this is unbalanced in schizophrenia pathology.
NR1 mRNA and protein is reduced in subjects with schizophrenia.
A small article but a big step forward.
The NMDA receptor has long been implicated in the pathophysiology of schizophrenia. In 1980, Kim et al. first put forward that glutamate levels may be altered in schizophrenia when they found decreased glutamate levels in the cerebrospinal fluid of schizophrenia sufferers.
This was later supported by studies showing that pharmacological blockade of the NMDA receptor caused psychotic symptoms in healthy people that are so alike to schizophrenia that it is often difficult to distinguish (see Javitt et al., 1991; Krystal et al., 1994; Lahti et al., 1995). The same treatment also significantly intensified the pre-existing symptoms of schizophrenia sufferers.
Hence, the glutamatergic system subsequently came under scrutiny by researchers.
Stemming from these studies, the NMDA receptor hypofunction hypothesis posits that dysregulation of glutamate is caused by NMDA receptor hypofunction on neurons of GABA subtype in subcortical regions. This leads to disinhibition of glutamatergic efferents destined for the cortex, causing a hyperglutamatergic state (see Marek et al., 2010). This theory is powerful, as it appears to account for all schizophrenia symptom profiles (positive, negative and cognitive).
It should be noted that although the NMDA receptor is widely implicated in glutamatergic dysfunction, it is unlikely that it is the solitary aetiological factor. Still, evidence suggests that many schizophrenia risk factors converge on the NMDAR rendering it of primary concern (see Kantrowitz and Javitt, 2010).
Therefore, the reductions of NR1 subunits reported by the Weickert team are in line with the glutamatergic hypothesis, providing compelling evidence that NMDA receptors are down regulated to accommodate for excess glutamate levels in the cortex. Hence, the manifestation of schizophrenia symptoms, especially cognitive dysfunction (as demonstrated in the antemortem findings of the present study), probably hinge on the NMDA receptor.
As cognitive dysfunctions remain largely untreated by current pharmacotherapies in many patients with schizophrenia, this study endorses the pursuit of novel therapeutics to reverse NMDA receptor hypofunction in the cortex of schizophrenia sufferers.
Reference: Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry. 2012 Oct 16.
To read this article, visit: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2012137a.html