twin studies have proved that neurodevelopmental disorders , such as attention deficit hyperactivity disorder ( adhd ) , autism spectrum disorders ( asd ) , as well as psychiatric conditions like schizophrenia ( scz ) and bipolar disorder ( bd ) have an important genetic background .
nevertheless , until very recently , causal genes have only been found in the context of intellectual disability ( i d ) .
classical genetic studies have failed to identify genes with high penetrance in pndd , thus indicating that the genetic background of these disorders is highly heterogeneous .
recent developments in dna analysis and sequencing , such as next - generation sequencing , snp arrays , exome sequencing or analysis of copy number variations ( cnvs ) , allow to study the whole genome of large cohorts of affected individuals , enabling the analysis of cns disorders with highly heterogeneous genetic etiology .
several of these studies have focused on pndds , uncovering new genes with potential roles in these disorders .
interestingly , many of the genes identified are involved in synaptic physiology , pointing towards synaptic dysfunction as an important contributing factor in many of these disorders .
although numerous psychiatric conditions have traditionally been ascribed to unbalances in monoaminergic systems , it is also accepted that alterations in the glutamatergic system are involved in these disorders .
in particular , an important group of genes expressed at the synapse identified in the context of pndds code for glutamate receptor subunits .
glurs comprise three families of ionotropic receptors : ampa ( -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ) , nmda ( n - methyl - d - aspartate ) and kainate ; as well as three groups of metabotropic receptors ( mglurs i - iii ) .
ionotropic receptors are found as tetramers of various subunits : 4 gria genes code for ampa subunits , 7 grin genes code for nmda subunits and 5 grik genes code for kainate subunits
. finally , metabotropic receptors , which are g - protein coupled receptors , are coded by 8 grm genes .
functionally , ionotropic glurs are specialized on different aspects of synaptic transmission . while nmda receptors act as coincident detectors of postsynaptic membrane depolarization and glutamate release , ampa receptors mediate fast transmission in excitatory synapses .
we discuss recently identified mutations in glur subunits in the context of pndds , including large genomic rearrangements directly affecting these genes or point mutations predicted to be deleterious .
linkage and association studies of natural variation , such as snps or microsatellites , have not been included in this work as these have a less direct implication in disease .
of all four genes coding for ampa receptor subunits , only mutations in gria2 and gria3 have been related with pndds ( table 1 ) .
alterations in these two genes have been associated with some cases of asd , but have mainly been found concomitant with i d .
although chromosomal deletions encompassing gria2 had been described for individuals with mental and developmental retardation ( see ref . 

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 for review ) , only recent studies have identified specific mutations in gria2 in the context of i d , suggesting that gria2 haploinsufficiency might cause i d .
gria3 was first identified as a candidate gene for x - linked i d in 1999 , in a female with a balanced translocation directly involving this gene . since then , several other gria3 mutations have been associated with i d , including complete or partial duplications , mutations on its 5utr and a whole gene deletion .
interestingly , both duplications and deletions of gria3 , translate into a diminished or absent synthesis of glua3 protein .
partial duplications would cause either reduced gria3 transcripts or aberrant protein levels ultimately contributing to i d .
missense gria3 variants have also been found linked to i d and , with the exception of the g833r mutation ( see table 1 ) these individuals express gria3 at normal levels . nevertheless , when functionally tested glua3 variants displayed altered channel function either in homomeric combination or in heteromers with normal glua2 .
glua3 is normally present at synapses together with glua2 contributing to the normal cycling of ampa receptors . from the studied individuals with i d
, it can be inferred that the lack of glua3 is not crucial for neuronal viability .
in fact , synaptic targeting and function of these receptors are not significantly altered in glua3 ko mice . remarkably , long - term potentiation ( ltp ) , widely thought to be the cellular basis of learning processes , is abnormal in these animals . nevertheless , in humans , the lack of glua3 could impair normal neuronal wiring or stabilization of activated synapses during development .
ampa receptor auxiliary subunits , tarps and cnihs , control receptor function by modulating channel trafficking and kinetics .
it is interesting to note that a mutation affecting cacng2 ( tarp -2 ) has been described in an individual with moderate i d .
this mutation caused a decreased association with ampa subunits , altering the receptor trafficking and reducing mepscs in hippocampal neurons .
finally , cnih2 deletion has also been found in a boy with mild i d .
thus , it is noteworthy that malfunctions of ampa receptor auxiliary can also be associated with i d .
these receptors are composed of two obligatory subunits ( glun1 ) and two variable ones , which consist of either glun2(a - d ) or glun3(a , b ) . of the variable subunits ,
glun2b expression starts very early in development and is critical for synaptogenesis and neuronal survival in cortical brain areas , thus making it a candidate factor in neurodevelopmental disorders .
indeed , grin2b is the most frequently mutated grin gene ( see table ) in pndds , being mainly related with i d .
specific grin2b gain - of - function mutations have also been associated with asd , supporting the hypothesis of an imbalance between excitatory and inhibitory neurotransmission in asd etiology , as well as in west syndrome with severe developmental delay . 

grin2a de novo mutations and microdeletions have also been associated to i d , indicating the viability of glun2a haploinsufficiency .
likewise , a rare grin2a de novo mutation was recently associated with schizophrenia , although the role of glun subunits with scz is under debate .
although less frequently , mutations in grin1 gene , the obligatory nmda receptor subunit , have also been identified . a mutation in grin1 has been found to cause non - syndromic intellectual disability ( nsid ) , an observation functionally validated using cellular models .
interestingly , regarding grin2c , grin3a and grin3b , only rare truncating mutations affecting both healthy individuals and asd / sz patients have been reported .
in contrast , no truncating mutations were found in grin1 , grin2a , grin2b and grin2d genes , suggesting a more critical function of these genes during neurodevelopment and the lethality of the putative loss - of - function .
taken together , these recent reports suggest that de novo mutations of nmdar subunits are frequently associated with i d , although some specific mutations are also associated with psychiatric diseases .
previous classic genetic association studies suggested linkages to mood disorders for some of the kainate receptor - encoding genes , mainly grik2 and grik3 ( see ref . 

more recently , cnvs in grik2 were found enriched in , but not exclusive of , children with i d , indicating limited pathogenic burden .
interestingly , a complex loss - of - function mutation in grik2 was found to co - segregate with nsid .
this grik2 mutation involves various deletions and inversions spanning exons 7 to 11 , resulting in loss of the first ligand - binding domain , the adjacent transmembrane domain , and the putative pore loop of gluk2 .
this study strongly indicates that loss of gluk2 protein can cause severe - to - moderate cognitive impairment in humans .
a grik4 variant with an insertion - deletion in the 3utr region ( which results in increased gluk4 levels ) was found to confer protection against bipolar disorder . moreover , this grik4 variant increased hippocampal activation during face processing , suggesting a link between kainate receptor - mediated excitation in the hippocampus and bipolar disorder .
so far , the subfamily of kainate glutamate receptors is the one for which less mutations have been identified in the context of pndds .
however , collectively taken , these results support the notion that mutations leading to up- or down - regulation of kainate subunits can cause learning disabilities and modulate mood disorders .
currently , a limited number of papers report deleterious mutations related to pndds in grms ( see table 1 ) . of these ,
two performed grm1 exon sequencing in scz and bd , another sequences the grm3 gene in a cohort of individuals with bd and one performed a genome - wide copy number variation ( cnv ) association study on attention deficit hyperactivity disorder ( adhd ) .
finally , a mutation in the kozak s sequence of grm3 assocaited with scz has also been reported .
i d , intellectual disability ; nsid , non - syndromic i d ; asd : autism spectrum disorder ; bd , bipolar disorder ; scz , schizophrenia ; adhd , attention deficit hyperactivity disorder ; * copy number variation study with average cnv size of 62 kb it is important to highlight that , as it happens with genes giving susceptibility to psychiatric diseases , none of the reported mutations supports for a causal role in disease . in most cases ,
the small number of mutations identified for grms make it still difficult to conjecture on their relevance to disease .
nevertheless , a striking observation can be made : there is no report implicating grm mutations in neurodevelopmental disorders such as i d or asd . despite the extensive literature on the role of these receptors , especially grm1 and grm5 , in fragile x - syndrome and asd , deleterious mutations on grms
have so far been found only in the context of psychiatric disorders , such as scz , bp or adhd .
recently developed dna analysis tools are allowing for the rapid uncovering of glurs mutations in the context of pndds .
this can be seen by the exponential increase in the number of papers reporting glur mutations in most recent years .
based on this , we expect that new glur mutations will be identified in the future , hopefully allowing for a better understanding of glur etiological contribution to pndds .
although the number of studies reporting glur mutations in pndd is so far restricted , some initial conclusions can be drawn .
these will need to be examined in the light of future studies . in the first place ,
mutations of subunits of some receptor subtypes are related to certain disease types but not to others . in this
regard , mutations in ampa subunits have only been found in the context of i d and asd , both neurodevelopmental disorders .
similarly , mutations in genes coding for ampar auxiliary proteins are also related with i d .
along these lines , mutations in nmda subunits are mostly linked to i d and asd . in stark contrast , mutations in metabotropic receptors are only related to psychiatric disorders .
accordingly , the data available would suggest that mutations in ionotropic glutamate receptors predispose towards neurodevelopmental disorders , while mutations in metabotropic receptors would predispose towards psychiatric disorders .
one can also draw a parallel between the extent of mental disability and the contribution to neurotransmission of the affected receptor type .
thus , loss - of - function mutations in ampa and nmda subunits are frequently found in patients with i d .
this is consistent with their important role in neuronal development , fast transmission , and synaptic plasticity . on the other hand ,
the abundance of grm mutations in individuals with psychiatric disorders is consistent with the more modulatory role of mglurs .
the occurrence of i d in carriers of a mutant gluk2 suggests that tuning of neuronal network activity by kainate receptors can have profound effects on cognitive abilities .
while some genes accumulate many potentially deleterious mutations , no mutations have been found in others . amongst ampa subunits , for instance , gria1 and gria4
have not been found mutated in the context of pndd , while twelve different mutations have been described for gria3 .
remarkably , the spectrum of mutations in nmda subunits concentrates in particular coding regions , namely , the extracellular and pore - forming domains .
this observation suggests that impaired ion selectivity and conductance of nmda receptors is closely linked to developmental defects , while the role of its intracellular tail might have a less critical role in disease .
there are several potential explanations why some glur genes do not appear mutated in relation to disease ; they might play indispensable biological functions , thus leading to lethality even in heterozygosity , or other molecules could compensate for their dysfunction .
interestingly , we do not see an increased number of mutations in glur subunits expressed early in development , which a priori , should be more relevant to neurodevelopmental disorders .
for instance , a similar number of mutations has been found for grin2b , which starts to be expressed early in development , and for grin2a , that is expressed post - natally .
in contrast , no mutations have been described for gria4 , also highly expressed during development .
nevertheless , this observation should be taken cautiously as mutations in developmental genes could cause lethality and also because gene expression data , mostly obtained from rodent species , might not be completely valid for humans .
although the etiopathology of pndds is complex and multigenic , a growing set of genetic and functional evidences indicate the contribution of glutamate receptors in these damaging disorders .
the following years will be crucial to understand whether the different receptor subunits are associated with certain pndds or not , as well as their interaction with genetic background and environmental factors .
 alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders ( pndd ) , but only recent advances in high - throughput dna sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors ( glur ) among afflicted individuals . in this review 
 we discuss recent work describing glur mutations in the context of pndds . 
 although there are no strict relationships between receptor subunit or type and disease , some interesting preliminary conclusions have arisen . 
 mutations in genes coding for ionotropic glutamate receptor subunits , which are central to synaptic transmission and plasticity , are mostly associated with intellectual disability and autism spectrum disorders . 
 in contrast , mutations of metabotropic glurs , having a role on modulating neural transmission , are preferentially associated with psychiatric disorders . also , the prevalence of mutations among glurs is highly heterogeneous , suggesting a critical role of certain subunits in pndd pathophysiology . 
 the emerging bias between glur subtypes and specific pndds may have clinical implications . 