The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

“…Together with recent reports of working memory deficits in mGlu 3 KO mice (43,44), the effects of mGlu 3 NAMs suggest that mGlu 3 plays an important role in certain PFC-dependent behaviors. Additionally, allelic variations in GRM3, the human gene encoding mGlu 3 , have been reported to affect prefrontal activity and cognitive performance in healthy human subjects (45) and several studies have found associations between mutations in GRM3 and psychiatric disorders (1,2,4,(6)(7)(8). If these mutations are found to lead to a loss of mGlu 3 function, this would suggest that selective positive allosteric modulators of mGlu 3 may represent a novel therapeutic strategy for enhancing prefrontal function in patients.…”

“…Additionally, these SNPs have also been associated with variations in functional magnetic resonance imaging (fMRI) indexes of prefrontal cortical activity during working memory tasks (1,3). Moreover, converging lines of evidence indicate that GRM3 represents a major locus associated with schizophrenia (1, 2, 4), bipolar disorder (5,6), and substance abuse disorders (6)(7)(8). Because mGlu 3 is densely expressed in PFC (9), a brain region implicated as a site of pathology in these disorders (10)(11)(12), this genetic evidence has led to an increased interest in determining the role of mGlu 3 in regulating PFC function and behavior.…”

Genomic responses to selection for tame/aggressive behaviors in the silver fox (Vulpes vulpes)

“…http://dx.doi.org/10.1101/228544 doi: bioRxiv preprint first posted online Dec. 4, 2017; heterozygosity and increased divergence between populations which was identified in the 157 analysis of re-sequenced genomes (34 (35,36). In our exonic SNP data, GRM3 has a C to G change causing a Wnt4 in the fox had more than one SNP with significant allele frequency changes.…”

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…1,2 Although initial trials with mGluR2/3 agonists have had mixed results, [3][4][5][6][7] data increasingly indicate that changes in mGluR3 are associated with schizophrenia and aging, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] encouraging this treatment strategy. Clinical trials were originally based on data from rodent models.…”

“…45,46 Insults to disrupted in schizophrenia 1 and phosphodiesterase 4A are linked to increased risk of illness. 47,48 Importantly, genetic alterations in mGluR3 are increasingly linked to schizophrenia, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] including altered dlPFC activation and poorer cognitive performance. 9,11 In particular, there is reduced mGluR3 protein in schizophrenia dlPFC, and an increase in GCPII, the enzyme that catabolizes the endogenous mGluR3 ligand, NAAG.…”