7 November 2012. Despite abundant indirect evidence implicating N-methyl-D-aspartate receptors (NMDARs) in positive and cognitive symptoms of schizophrenia, it has proved surprisingly difficult to identify structural or functional differences in these receptors in the disorder, leading many researchers to try to account for these findings by studying signaling mechanisms downstream of NMDARs. A new study, led by Tom Weickert of Australia’s University of New South Wales, examined NMDAR subunits in the largest postmortem cohort to date, finding reduced expression of the NR1 and NR2C subunits. The study, published online on October 16 in Molecular Psychiatry, also linked a single-nucleotide polymorphism (SNP) in the gene coding for the NR2B subunit to both poor cognitive performance and reduced expression of the NR1 subunit in the dorsolateral prefrontal cortex of schizophrenia subjects.
NMDARs are activated by glutamate, the brain’s primary excitatory neurotransmitter, but also require co-activation by either D-serine or glycine. They play a myriad of roles throughout the nervous system, from neurodevelopment to learning and memory (see SRF related news story). Their versatility is made possible by a complex mix-and-match configuration: two obligatory glycine-binding NR1 subunits, which occur in eight variants via alternative splicing of the gene GRIN1, are paired with two glutamate-binding NR2 subunits, which have four isoforms (NR2A-D), and/or with two glycine/D-serine-binding NR3 subunits, which have two isoforms (NR3A and NR3B).
It has been known for decades that NMDAR antagonists such as phencyclidine (PCP) and ketamine have potent psychotomimetic effects in healthy subjects and worsen symptoms in those with schizophrenia, providing the first clues that NMDAR hypofunction might contribute to the psychosis seen in the illness (see SRF Current Hypotheses by Bita Moghaddam and Daniel Javitt). Reduced serum levels of the endogenous NMDAR agonist D-serine (Hashimoto et al., 2003), as well as increased activity of D-amino acid oxidase (Madeira et al., 1997), which degrades D-serine, have been reported in schizophrenia, but reports of NMDAR expression in postmortem tissue have yielded mixed results—with increased, decreased, and unchanged levels reported (Kristiansen et al., 2007).
In the current study, first author Cynthia Weickert and colleagues measured mRNA transcripts for the NR1, NR2A, NR2B, NR2C, and NR3A NMDAR subunits, as well as NR1 protein levels, in postmortem samples of dorsolateral prefrontal cortex (DLPFC) from schizophrenia subjects and matched controls. Levels of NR1 and NR2C mRNA were significantly lower—22 percent and 28 percent, respectively—in schizophrenia subjects’ DLPFC, and NR1 protein levels were significantly lower by 36 percent.
In a second component of the new study, the research team found that subjects with schizophrenia carrying the minor allele (C) of the NR2B gene SNP rs1805502 had significantly lower reasoning performance, as measured by the Arithmetic Subtest of the Weschler Adult Intelligence Scale (WAIS-III), than both schizophrenia subjects who did not carry the C allele and controls who did. In further postmortem analyses, the group found that NR1 mRNA and protein levels were significantly lower in C carrier schizophrenia subjects than C carrier controls, but no change was observed between control and schizophrenia subjects who did not carry the C allele. NR2C mRNA levels did not differ as a function of rs1805502 genotype in either controls or subjects with schizophrenia.
The significant reduction of both mRNA and protein of the obligatory NR1 subunit, “supports the theory,” the authors write, “that hypofunction of NMDARs exists endogenously in prefrontal cortex in schizophrenia and strongly supports that the hypofunction can reside within the NMDAR.” Weickert and colleagues argue that their NR2C findings may also speak to the cognitive deficits of schizophrenia, citing research showing deficits in fear conditioning and working memory in NR2C-knockout mice (Hillman et al., 2011).
The exact mechanism by which the NR2B SNP produces lower NR1 levels and cognitive deficits in schizophrenia remains unknown. Interestingly, although a SNP in NR1 that has previously been associated with schizophrenia (Zhao et al., 2006) was not associated with lower NR1 levels in the current study, one schizophrenia study has demonstrated a genetic interaction between the NR1 and NR2B SNPs (Qin et al., 2005).—Pete Farley.
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. Abstract