Glutamate receptors in domestication and modern human evolution

GRIK3 and GRM8 were two of only three genes to show signals of selection across four different species (including modern humans), the third being ADGRB3.

“GRIK3 and GRM8 were two of only three genes to show signals of selection across four different species (including modern humans), the third being ADGRB3.”

The analysis highlights prevalent changes to glutamate receptor genes, most notably kainate and metabotropic receptor genes.

“This analysis highlights prevalent changes to glutamate -most notably kainate and metabotropic -receptor genes.”

At least one glutamate receptor gene shows signals of selection in each species for which such studies have been carried out, except the yak.

“At least one glutamate receptor gene shows signals of selection in each of the species for which such studies have been carried out, with the exception of the yak (Table 1: selective sweeps highlighted in red).”

There were 213 signals of selection across all species, counting multiple detections of a gene in a single species as one signal.

“Where a given gene was detected in a selective sweep region across multiple studies for a single species, this was counted as a one signal, giving a total of 213 signals of selection across all species.”

Averaging across major receptor types, glutamate receptor genes fall within selective sweep regions at higher rates than receptor genes from any other primary neurotransmitter system in the brain.

“Averaging across major receptor types, as defined by their endogenous ligands, glutamate receptor genes fall within selective sweep regions at higher rates than receptor genes from any of the other primary neurotransmitter systems in the brain (see Fig. 1a).”

Glutamate receptor genes fall within identified selective-sweep regions at considerably higher rates than any other major receptor type among the 488 receptor genes studied.

“Glutamate receptor genes fall within identified selective-sweep regions at considerably higher rates than any other major receptor type among the 488 receptor genes studied here (see Supplementary Table S1, Appendix A: mmc3).”

The chance likelihood of signals occurring at the rate they do on receptor families with comparable means (ADGRB, ADGRD, and corticosteroid) was considerably higher (p = 0.12, p = 0.265, and p = 0.265, respectively).

“By contrast, the chance likelihood of signals occurring at the rate they do on receptor families with comparable means (ADGRB, ADGRD, and corticosteroid) was considerably higher (p = 0.12, p = 0.265, and p = 0.265, respectively).”

An extended functional analysis of the 92 genes showing signals of selection in two or more species highlighted 'Glutamatergic synapse' as the second most prominent KEGG pathway, behind 'Neuroactive ligand-receptor interaction'.

“An extended functional analysis of the 92 genes showing signals of selection in two or more species highlighted 'Glutamatergic synapse' as the second most prominent KEGG pathway, behind the more general (and subsuming) category 'Neuroactive ligand-receptor interaction'.”

KIT was identified in four different species (showing signals of selection in cattle and sheep, of introgression in the yak, and of brain expression differences in the pig).

“Interestingly, KIT, a gene involved in the differentiation of neural crest precursor cells into melanocytes, and important in selection for coat color in domesticated species (Wilkins et al., 2014), was also identified in four different species (showing signals of selection in cattle and sheep, of introgression in the yak, and of brain expression differences in the pig).”

Under each of the measures in Tables S3-S12, the rates of signals occurring on glutamate receptor genes (in particular kainate and Group II/III metabotropic) consistently remain higher than those for other receptor types and (sub)families.

“Under each of the measures in Tables S3-S12, the rates of signals occurring on glutamate receptor genes (in particular kainate and Group II/III metabotropic) consistently remain higher than those for other receptor types and (sub) families.”

Three glutamate receptor genes (GRM7, GRIN3A, and GRIA2) were identified among the 10 genes with changes detected in three species.

“Three glutamate receptor genes (GRM7, GRIN3A, and GRIA2) were identified among the 10 genes with changes detected in three species.”

Of the eight receptor genes that show signals of selection across three or more different species, four are glutamate receptor genes (GRIK2, GRIK3, GRM8, and GRIA2).

“Of the eight receptor genes that show signals of selection across three or more different species (see Supplementary Table S1, Appendix A: mmc3), four are glutamate receptor genes (GRIK2, GRIK3, GRM8, and GRIA2).”

Out of the 22 pairwise comparisons that showed significant differences between means, twenty involved metabotropic subfamily III, while the two other significant comparisons involved the kainate receptor family.

“Out of the 22 pairwise comparisons that showed significant differences between means, twenty involved metabotropic subfamily III, while the two other significant comparisons involved the kainate receptor family (see Supplementary Table S14, Appendix A: mmc3).”

Both (sub)families, as well as glutamate receptor genes as a whole, fell within selective sweep regions at significantly higher rates than the seven receptor types when considered as a single group, surviving Bonferroni correction (p ≤ 0.00625).

“Both (sub)families, as well as glutamate receptor genes as a whole, fell within selective sweep regions at significantly higher rates than the seven receptor types when they were considered as a single group (the significant difference surviving Bonferroni correction [p ⩽ 0.00625], see Table 1a).”

As with the analysis taking only selective sweeps into account, glutamate receptor genes, and especially metabotropic II/III and kainate receptor gene (sub)families, showed significantly higher proportions of changes when compared with combined major receptor types.

“As with the analysis taking only selective sweeps into account, glutamate receptor genes, and especially metabotropic II/III and kainate receptor gene (sub)families showed significantly higher proportions of changes when compared with combined major receptor types (see Fig. 2a).”

• AssumptionRests on an assumption: Brain expression differences can serve as proxies for signals of selection at the level of biological pathways.

In terms of potential convergence between domesticated species and modern humans, signals were detected on members of kainate (GRIK3), metabotropic Group II (GRM3), Group III (GRM6, GRM7, GRM8), NMDA (GRIN2D, GRIN3A) and AMPA receptor genes (GRIA2) in at least one domesticate and one modern-human study.

“In terms of potential convergence between domesticated species and modern humans, signals were detected on members of kainate (GRIK3), metabotropic Group II (GRM3), Group III (GRM6, GRM7, GRM8), NMDA (GRIN2D, GRIN3A) and AMPA receptor genes (GRIA2) in at least one domesticate and one modern-human human study (see Table 1).”

Changes on Group III metabotropic receptor genes are identified at a rate higher than those of any other multigene receptor (sub)families (mean of 2.75 signals per gene), including receptor genes for GABA, serotonin, (nor)epinephrine, acetylcholine, or dopamine.

“Changes on Group III metabotropic receptor genes are identified at a rate higher than those of any other multigene receptor (sub)families (mean of 2.75 signals per gene)”

When all measures (allele frequency divergence, adaptive introgression, or brain expression changes) are included, a total of 401 putative signals were identified across the 488 genes (a receptor-wide mean of 0.82 signals per gene).

“When all such measures are included, a total of 401 putative signals were identified across the 488 genes (a receptor-wide mean of 0.82 signals per gene).”

GRIK2 and GRM8 were two of only five genes that were identified in four domesticates (including modern humans in the case of GRM8) (likelihood according to Monte Carlo simulation: p = 0.043).

“GRIK2 and GRM8 were two of only five genes that were identified in four domesticates (including modern humans in the case of GRM8) (likelihood according to Monte Carlo simulation: p = 0.043).”

The only exception to the concentration of metabotropic receptor changes in Group II or Group III subfamilies is the detection of a selective sweep on GRM1 in the chicken.

“The only exception to this is the detection of a selective sweep on GRM1 in the chicken.”

Out of the 19 instances where selective sweeps, expression differences, allele-frequency changes, or adaptive introgression were detected on metabotropic receptor genes in a given study, 18 occurred in Group II or Group III subfamilies.

“Out of the 19 instances where selective sweeps, expression differences, allele-frequency changes, or adaptive introgression were detected on metabotropic receptor genes in a given study, 18 occurred in Group II or Group III subfamilies.”

There are cross-species parallelisms in the expression of kainate and metabotropic receptors.

“Broadly, there are crossspecies parallelisms in the expression of kainate and metabotropic receptors.”

Relative to kainate receptors, metabotropic receptors show higher expression in the amygdala and hypothalamus.

“Relative to kainate receptors, they show higher expression in the amygdala and hypothalamus.”

Kainate receptors highlighted here are most prominently expressed in the hippocampal formation (hippocampus and entorhinal cortex) in prenatal and early postnatal periods.

“The kainate receptors highlighted here are most prominently expressed in the hippocampal formation (hippocampus and entorhinal cortex) in prenatal and early postnatal periods.”

Morphological differences between modern and archaic Homo resemble those of domesticated species compared with their wild counterparts.

“It has long been noted that morphological differences between modern and archaic Homo resemble those of domesticated species when compared with their wild counterparts (Boas, 1938).”

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Prevalent overlapping signals of selection in domesticates (dogs, cats, cattle, and horses) and anatomically modern humans occur on glutamatergic signaling genes.

“In earlier work, we have shown that prevalent overlapping signals of selection in domesticates (dogs, cats, cattle, and horses) and anatomically modern humans (AMH) occur on glutamatergic signaling genes (Theofanopoulou et al., 2017).”

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Glutamate signaling genes are widely expressed in tissues beyond the CNS, including osteoblasts, osteoclasts, melanocytes, and chondrocytes.

“Glutamate signaling genes are also widely expressed in tissues beyond the CNS, including osteoblasts, osteoclasts, melanocytes, and chondrocytes (Wang et al., 2005;Hoogduijn et al., 2006;Devi et al., 2013;Julio-Pieper et al., 2011;Matta, 2013).”

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• cites Hoogduijn et al., 2006 sourceNot checked yet

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• cites Devi et al., 2013 sourceNot checked yet

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The evidence suggests an important role for kainate and metabotropic receptors in regulating hypothalamic-pituitary-adrenal axis excitation.

“This evidence suggests an important role for kainate and metabotropic receptors in regulating hypothalamic-pituitary-adrenal axis excitation, and we provide a mechanistic account of their actions in attenuating the stress response.”

ADGRB3 is implicated in similar neurodevelopmental and stress disorders as kainate and metabotropic glutamate receptors.

“ADGRB3 is implicated in similar neurodevelopmental and stress disorders as kainate and metabotropic glutamate receptors (reviewed further below and in detail in Supplemetary Information: Section S2 [Appendix A: mmc1]) (Lanoue et al., 2013).”

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Synaptic proteins, including glutamate receptors, are rarely subject to extensive structural changes from one species to the next.

“Given their importance for the normal functioning of the organism, synaptic proteins, including glutamate receptors, are rarely subject to extensive structural changes from one species to the next (Bayés et al., 2011;Ryan and Grant, 2009;Goto et al., 2009;Wada et al., 2004).”

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• cites Goto et al., 2009 sourceNot checked yet

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These findings suggest that signals on metabotropic III and kainate receptor (sub)families are, at least, significantly higher than background genome-wide signals of selection under domestication.

“When one considers that alterations to neurotransmission are highlighted in many of the domestication studies analyzed here, these findings suggest that signals on metabotropic III and kainate receptor (sub)families are, at least, significantly higher than background genome-wide signals of selection under domestication.”

The above analyses are suggestive that glutamatergic signaling has been disproportionately targeted by selective pressures in modern human evolution and domestication.

“The above analyses are suggestive that glutamatergic signaling has indeed been disproportionately targeted by selective pressures in modern human evolution and domestication.”

• AssumptionRests on an assumption: Convergent genomic signals across domesticated species and modern humans indicate convergent evolutionary paths or shared selective pressures.

The extent to which CNS-expressed glutamate receptor genes are identified in this review marks them as prime candidates for involvement in the emergence of domesticated and modern human behavioral phenotypes, in particular tameness and the reduction of reactive aggression.

“The extent to which these CNS-expressed receptor genes are identified in our review marks them as prime candidates for involvement in the emergence of domesticated and modern human behavioral phenotypes, in particular tameness and the reduction of reactive aggression.”

• AssumptionThe authors state this as an assumption: No study to date has explored the extent to which glutamate receptor genes are associated with recent evolutionary events across a large number of domesticates and with the emergence of our own species.
• AssumptionThe authors state this as an assumption: No previous study has identified kainate and metabotropic receptor genes among the most prevalent targets of selective sweeps in domestication and recent human evolution.

Humans exhibit highly reduced reactive aggression among conspecifics compared with other extant primates.

“Humans exhibit highly reduced reactive aggression among conspecifics compared with other extant primates, and it has recently been proposed that this potentially convergent attenuation of aggressive reactivity came under further positive selection during our recent evolution (Wrangham, 2019).”

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Changes to regulatory regions may have had important functional consequences for the emergence of the human cognitive phenotype.

“suggesting that changes to regulatory regions may have had important functional consequences for the emergence of the human cognitive phenotype.”

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• cites Muntané et al., 2015 sourceNot checked yet

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There are significant differences between humans and chimpanzees in the cortical expression of glutamate receptor genes.

“Despite this high structural conservation, there are significant differences between humans and chimpanzees in the cortical expression of glutamate receptor genes (Liu et al., 2012;Muntané et al., 2015), suggesting that changes to regulatory regions may have had important functional consequences for the emergence of the human cognitive phenotype.”

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A large proportion of selective sweeps or high-frequency changes on glutamate receptor genes in AMH relative to archaic Homo are found in regulatory regions that control gene expression.

“Similarly, a large proportion of selective sweeps or highfrequency changes on glutamate receptor genes in AMH relative to archaic Homo are found in regulatory regions that control gene expression (Peyrégne et al., 2017;Kuhlwilm and Boeckx, 2019).”

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• cites Kuhlwilm and Boeckx, 2019 sourceNot checked yet

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Kainate and Group II/III metabotropic receptors have predominantly modulatory or inhibitory, as opposed to purely excitatory, effects on signaling.

“Kainate and Group II/III metabotropic receptors have predominantly modulatory or inhibitory, as opposed to purely excitatory, effects on signaling: kainate receptors are both presynaptically and postsynaptically located.”

The association of kainate and Group II/III metabotropic receptor genes with multiple stress disorders implicates them in altered HPA-axis activity.

“The association of kainate and Group II/III metabotropic receptor genes with multiple stress disorders implicates them in altered HPA-axis activity, and there is evidence for this involvement from early developmental stages.”

Schizophrenia is among the disorders most regularly associated with mutations on metabotropic and kainate receptor genes.

“Schizophrenia is among the disorders most regularly associated with mutations on metabotropic and kainate receptor genes.”

In humans, prenatal stress is a prominent risk factor for the development of schizophrenia in adult offspring.

“In humans, prenatal stress is a prominent risk factor for the development of schizophrenia in adult offspring (van Os and Selten, 1998;Koenig et al., 2002).”

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The broad range of functions of kainate and Group II/III metabotropic receptors makes them plausible candidates for attenuating excitatory inputs to the HPA and reducing stress responses in humans and (pre-)domesticated species.

“The broad range of functions of kainate and Group II/III metabotropic receptors makes them plausible candidates for attenuating excitatory inputs to the HPA and reducing stress responses in humans and (pre-)domesticated species.”

Pharmacological agonists of Group II metabotropic receptors reduce schizophrenia-like phenotypes in adult offspring of prenatally stressed mice.

“Pharmacological agonists of Group II metabotropic receptors reduce schizophrenia-like phenotypes in adult offspring of prenatally stressed mice (Matrisciano et al., 2012).”

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High glucocorticoid inputs from the adrenal gland to the hippocampus reduce the expression of kainate receptors.

“Furthermore, high glucocorticoid inputs from the adrenal gland to the hippocampus reduce the expression of kainate receptors, and schizophrenics have been found express significantly reduced kainate receptors in this region (Hunter et al., 2009;Benes et al., 2001).”

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Schizophrenics express significantly reduced kainate receptors in the hippocampus.

“and schizophrenics have been found express significantly reduced kainate receptors in this region (Hunter et al., 2009;Benes et al., 2001).”

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Domesticated foxes, sheep, Bengalese finches, and ducks have lower basal GC levels than their wild ancestors or other closely related wild comparators.

“Domesticated foxes, sheep, Bengalese finches, and ducks have lower basal GC levels than their wild ancestors or other closely related wild comparators (Plyusnina et al., 1991;Naumenko et al., 1989;Bassett and Hinks, 1969;Turner, 1984;Suzuki et al., 2014;Martin, 1975Martin, , 1978)).”

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• cites Naumenko et al., 1989 sourceNot checked yet

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• cites Bassett and Hinks, 1969Not checked yet

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Metabotropic and kainate receptor genes may mediate the effects of environmental stressors on the organism.

“but also that these genes may mediate the effects of environmental stressors on the organism.”

Human infants born preterm that exhibit an atypical neurobehavioral profile have significantly differential methylation of GRIK3 when compared with infants showing a more typical neurobehavioral profile.

“Similarly, human infants born preterm that exhibit an atypical neurobehavioral profile, including poor attention, self-regulation, and quality of movement, as well as increased arousal, excitability, and systemic signs of prenatal stress, have significantly differential methylation of GRIK3 when compared with infants showing a more typical neurobehavioral profile (Everson et al., 2019).”

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Prenatal stress can contribute to the emergence of the same neurodevelopmental, neuropsychiatric, stress, and mood disorders that are commonly associated with altered expression of metabotropic and kainate receptor genes.

“Thus, not only is there evidence that prenatal stress can contribute to the emergence of the same neurodevelopmental, neuropsychiatric, stress, and mood disorders that are commonly associated with altered expression of metabotropic and kainate receptor genes, but also that these genes may mediate the effects of environmental stressors on the organism.”

In prenatally stressed cattle, GRIK3 has recently been identified among genes with the most significant hypomethylation of intronic CpG sites, a process thought to downregulate gene expression.

“In prenatally stressed cattle, GRIK3 has recently been identified among genes with the most significant hypomethylation of intronic CpG sites, a process thought to downregulate gene expression (Littlejohn et al., 2018).”

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GC measures can be an accurate indicator of stress response in vertebrates, once basal and stress-response measures can be differentiated.

“Thus, GC measures can be an accurate indicator of stress response in vertebrates, once basal and stress-response measures can be differentiated (Jacobson and Sapolsky, 1991).”

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Alterations to the HPA axis are considered to be essential for the emergence of tameness in different theories of domestication.

“Alterations to the HPA axis are considered to be essential for the emergence of tameness in different (indeed competing) theories of domestication (Wilkins et al., 2014;Belyaev, 1979).”

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• cites Belyaev, 1979 sourceNot checked yet

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Compared to their wild ancestors, Guinea pigs and chickens have a lower spike in GCs in response to stress.

“Compared to their wild ancestors, Guinea pigs and chickens have a lower spike in GCs in response to stress (Künzl and Sachser, 1999;Ericsson et al., 2014).”

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Proactively aggressive or non-aggressive children tend to have a lower spike in GC levels in response to frustrating tasks than reactively aggressive children.

“Proactively aggressive or non-aggressive children tend to have a lower spike in GC levels in response to frustrating tasks than reactively aggressive children (Lopez-Duran et al., 2009).”

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Decreased GC spikes in response to stress are common to domesticates and non-aggressive or proactively aggressive modern humans versus reactively aggressive individuals.

“Moreover decreased GC spikes in response to stress are common to domesticates and non-aggressive or proactively aggressive modern humans versus reactively aggressive individuals.”

From early development into adulthood, lower basal GC levels are shared by domesticates and modern humans relative to closely related extant wild species.

“The above studies suggest that, from early development into adulthood, lower basal GC levels are shared by domesticates and modern humans relative to closely related extant wild species.”

Prosocial selective pressures have led to a reduction in reactive over and above proactive aggression in recent human evolution.

“These findings are consistent with the view that prosocial selective pressures have led to a reduction in reactive over and above proactive aggression in recent human evolution (Wrangham, 2018).”

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Psychopathic adults tend to have no cortisol reactivity to frustrating tasks.

“Psychopathic adults (who often exhibit pathological proactive aggression) tend to have no cortisol reactivity to frustrating tasks (Haller, 2014).”

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The PVN is the crucial hypothalamic mediator of psychogenic stressors that drive HPA activity.

“The PVN is the crucial hypothalamic mediator of psychogenic stressors that drive HPA activity.”

Feedforward mechanisms, further potentiating the stress response, are relayed from the amygdala to the PVN via the BNST.

“Feedforward mechanisms, further potentiating the stress response, are relayed from the amygdala to the PVN via the BNST.”

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The HPA axis is centrally regulated by the limbic system, primarily through amygdalar processing of perceptual inputs, which are relayed via the bed nucleus of the stria terminalis to the paraventricular nucleus in the hypothalamus.

“The HPA axis is centrally regulated by the limbic system, primarily through amygdalar processing of perceptual inputs, which are relayed via the bed nucleus of the stria terminalis (BNST) to the paraventricular nucleus (PVN) in the hypothalamus.”

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Suppression of glutamatergic signaling by both kainate and metabotropic glutamate receptors in the PVN may serve to inhibit direct activation of the stress-response cascade.

“This means that suppression of glutamatergic signaling by both kainate and metabotropic glutamate receptors in the PVN may serve to inhibit direct activation of the stressresponse cascade.”

In macaques captured from the wild, six-week chronic intravenous administration of a Group II agonist reduced basal cortisol levels by as much as 50% compared to controls.

“In macaques captured from the wild, six-week chronic intravenous administration of a Group II agonist reduced basal cortisol levels by as much as 50% compared to controls (Coplan et al., 2001).”

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GRIK5 is extensively expressed on parvocellular neurons.

“GRIK5 is extensively expressed on parvocellular neurons (Aubry et al., 1996).”

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Group III metabotropic receptors inhibit excitatory inputs to the lateral hypothalamus.

“Group III metabotropic receptors have also been shown to inhibit excitatory inputs to the lateral hypothalamus (Acuna-Goycolea et al., 2004), while Group I metabotropic receptors stimulate both oxytocin and vasopressin release from the SON (Morsette et al., 2001).”

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Mice administered with Group II antagonists in vivo experienced an increase in corticosterone that mimicked the response to the forced-swim test.

“Mice administered with Group II antagonists in vivo experienced an increase in corticosterone that mimicked the response to the forcedswim (behavioral despair) test (Scaccianoce et al., 2003).”

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Group II receptors are implicated in the attenuation of central glutamatergic inputs to the hypothalamus (likely in the PVN), attenuating the HPA stress response.

“Given their predominant presynaptic and glial inhibitory functions, the above evidence implicates Group II receptors in the attenuation of central glutamatergic inputs to the hypothalamus (likely in the PVN), attenuating the HPA stress response.”

A Group II agonist acts on GRM3 receptors in adrenal gland cells, leading to a reduction in aldosterone and cortisol via inhibition of the adenylyl cyclase/cAMP signaling pathway.

“This same agonist has been shown to act on GRM3 (mGluR3) receptors in adrenal gland cells, leading to a reduction in aldosterone and cortisol via inhibition of the adenylyl cyclase/cAMP signaling pathway (Felizola et al., 2014).”

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Group I metabotropic receptors stimulate both oxytocin and vasopressin release from the SON.

“while Group I metabotropic receptors stimulate both oxytocin and vasopressin release from the SON (Morsette et al., 2001).”

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Knockout of GRM2 correlates with increased stress in social interactions.

“Knockout of GRM2 has been shown to correlate with increased stress in social interactions (Morishima et al., 2005).”

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Presynaptic activation of GRIK1 subunits in the PVN attenuates HPA activity by inhibiting CRH release from parvocellular neurons.

“Presynaptic activation of GRIK1 (GLuK1, GLUR5) subunits in the PVN has been shown to attenuate HPA activity by inhibiting CRH release from parvocellular neurons (Evanson and Herman, 2015).”

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Agonism of presynaptic kainate receptors in hypothalamic neurons facilitates inhibitory GABAergic signaling.

“Similarly, agonism of presynaptic kainate receptors in hypothalamic neurons facilitates inhibitory GABAergic signaling (Liu et al., 1999).”

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In a recent study of dissocial personality disorder, a rare duplication of GRM7 was associated with extreme impulsive violence in a male prisoner cohort.

“In a recent study of dissocial personality disorder, a rare duplication of GRM7 was associated with extreme impulsive violence in a male prisoner cohort (Vevera et al., 2019).”

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Mice lacking the Group III receptor subunit GRM8 display increased age- and sex-dependent anxiety-like behaviors and startle response.

“Mice lacking the Group III receptor subunit GRM8 (mGluR8) display increased age-and sex-dependent anxiety-like behaviors and startle response (Duvoisin et al., 2005(Duvoisin et al., , 2010)).”

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Excitatory feedback outputs from the hippocampus likely act on inhibitory neurons of the BNST that, in turn, relay to the hypothalamus.

“Excitatory feedback outputs from the hippocampus likely act on inhibitory neurons of the BNST that, in turn, relay to the hypothalamus (Herman and Cullinan, 1997).”

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Decreased Group II suppression of hippocampal outputs in response to stress can have the effect of enabling increases of inhibitory signals to dampen the HPA cascade.

“Thus, decreased Group II suppression of these outputs in response to stress can have the effect of enabling increases of inhibitory signals to dampen the HPA cascade.”

Activation of Group II receptors is downregulated in the hippocampus.

“At the same time, activation of Group II receptors is downregulated in the hippocampus (Zhao et al., 2006).”

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Within the BNST itself, activation of Groups II and III receptors suppresses excitatory transmission.

“Within the BNST itself, activation Groups II and III receptors has been shown to suppress excitatory transmission (Grueter and Winder, 2005).”

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Numerous signals of selection on GRM8 across domesticates and similar signals on Group II receptors in humans may be markers of convergent selection for a decreased stress response.

“This suggests that the numerous signals of selection on GRM8 across domesticates and similar signals on Group II receptors in humans may be markers of convergent selection for a decreased stress response.”

Kainate receptor activation at CA3-CA1 synapses serves to inhibit glutamate transmission via Gi/o signaling, especially when synapses are immature.

“Kainate receptor activation at CA3-CA1 synapses serves to inhibit glutamate transmission via G i/o signaling, especially when synapses are immature.”

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Both Group II and Group III metabotropic receptor subfamilies are important for regulating the stress response, including aggressive reactivity.

“Although the above behavioral correlates of Groups II and III receptor (ant-)agonism and ablation are partially contrasting, they indicate that both subfamilies are important for regulating the stress response, including aggressive reactivity.”

Acute corticosterone treatment in adrenalectomized rats lowers kainate receptor mRNA expression to levels of untreated controls.

“Acute corticosterone treatment in adrenalectomized rats lowers kainate receptor mRNA expression to levels of untreated controls (Joëls et al., 1996).”

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These divergent MR-/GR-mediated patterns of expression can help to elucidate the mechanism by which the genes under selection in domesticates and humans are expressed in a manner that can potentiate or attenuate the stress-induced feedback response.

“These divergent MR-/ GR-mediated patterns of expression can help to elucidate the mechanism by which the genes under selection in domesticates and humans are expressed in a manner that can potentiate or attenuate the stress-induced feedback response.”

Evidence points more clearly towards activation of Group II receptors in potentiating prosocial behaviors.

“This said, evidence also points more clearly towards activation of Group II receptors in potentiating prosocial behaviors.”

MR binding has been reported both to lower and raise GRIK2 levels in the hippocampus.

“MR binding has been reported both to lower and raise GRIK2 levels in the hippocampus (Hunter et al., 2009;Joëls et al., 1996).”

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• cites Joëls et al., 1996Not checked yet

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Glucocorticoids differentially modulate the expression of kainate receptor mRNA in the hippocampus depending on whether MRs or GRs are bound.

“Glucocorticoids differentially modulate the expression of kainate receptor mRNA in the hippocampus depending on whether MRs or GRs are bound (Joëls et al., 1996;Hunter et al., 2009).”

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• cites Hunter et al., 2009 sourceNot checked yet

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Postsynaptic expression of AMPA and NMDA is enhanced under acute stress and corticosterone treatment.

“In contrast, postsynaptic expression of AMPA and NMDA is enhanced under acute stress and corticosterone treatment (Popoli et al., 2011).”

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Increased facilitation of glutamate release during basal or low-level stress is likely to primarily innervate GABAergic neurons along pathways relaying to the PVN.

“In the case of kainate receptor expression, which is predominant in the hippocampus and medial prefrontal cortex, increased facilitation of glutamate release during basal or low-level stress is likely to primarily innervate GABAergic neurons along pathways relaying to the PVN.”

Kainate-receptor actions in the stress feedback regions of the hippocampus and mPFC are regulated by corticosteroid inputs.

“Kainate-receptor actions in the stress feedback regions of the hippocampus and mPFC are regulated by corticosteroid inputs.”

At higher GC levels, as when under acute stress, GR binding will tend to reduce kainate receptor expression, thus diminishing these receptors' ability to control glutamate release.

“At higher GC levels (as when under acute stress) GR binding will tend to reduce kainate receptor expression, thus diminishing these receptors' ability to control glutamate release.”

During moments of high stress, corticosteroids downregulate kainate receptor expression, reducing these receptors' abilities to attenuate excitatory signaling.

“During moments of high stress, corticosteroids downregulate kainatereceptor expression, reducing these receptors' abilities to attenuate excitatory signaling.”

Similar two-way modulation has been detected in the neocortex and amygdalae of rodents.

“Similar two-way modulation has been detected in the neocortex and amygdalae of rodents.”

GR binding during acute stress serves to diminish the alternate inhibitory effect of kainate receptors during intense glutamatergic release.

“GR binding during acute stress serves to diminish the alternate inhibitory effect of kainate receptors during intense glutamatergic release.”

The reduction in excitatory innervation of amygdalar GABAergic outputs limits GABA-on-GABA disinhibition of the BNST, which supplies the predominant inhibitory inputs to the PVN, the initiator of the HPA signaling cascade.

“The reduction in excitatory innervation of amygdalar GABAergic outputs limits GABA-on-GABA disinhibition of the BNST, which supplies the predominant inhibitory inputs to the PVN, the initiator of the hypothalamic-pituitary-adrenal (HPA) signaling cascade.”

Downregulation of kainate receptor expression by Groups II and III metabotropic receptors limits excitation of central and feedforward stress-response regions of the amygdala and PVN.

“Similarly, downregulation of kainate receptor expression by Groups II and III metabotropic receptors limit excitation of central and feedforward stress-response regions of the amygdala and PVN.”

When GCs are circulating at low levels, during basal or low stress, MR binding should lead to higher kainate receptor expression and facilitation of glutamatergic signaling in feedback regions.

“Thus, when GCs are circulating at low levels, during basal or low stress, MR binding should lead to higher kainate receptor expression and facilitation of glutamatergic signaling in feedback regions.”

Selection on KIT is unlikely to be related to the unifying domesticated trait of tameness, as proposed for the attenuation of glutamatergic signaling in stress-response regions of the brain.

“As such, selection on KIT is unlikely to be related to the unifying domesticated trait of tameness, as proposed here for the attenuation of glutamatergic signaling in stress-response regions of the brain.”

• AssumptionRests on an assumption: Selection for tameness is the unifying domesticated trait.

Groups II and III metabotropic and kainate receptors have been implicated in many disorders and phenotypes reviewed in the paper.

“These receptors have been implicated in many disorders and phenotypes reviewed here for metabotropic and kainate receptors (see Table 2 and Supplementary Information: Section S2).”

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• cites Supplementary Information: Section S2Not checked yet

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The present analysis of modern human-archaic and domesticate-wild differences in glutamatergic receptor genes suggests that any modifications to serotonin/oxytocin systems, particularly oxytocinergic signaling, are more likely to be dependent on upstream changes to glutamatergic signaling.

“The present analysis of modern human-archaic and domesticate-wild differences in glutamatergic receptor genes suggests that any such modifications (particularly to oxytocinergic signaling) are more likely to be dependent on upstream changes to glutamatergic signaling.”

• AssumptionRests on an assumption: The domesticated species and modern humans compared in the analysis have homologous stress-response brain regions and comparable glutamatergic signaling such that signals of selection can be meaningfully compared.

These overlaps in function very plausibly contribute to numerous signals of selection being spread across different metabotropic receptor genes in distinct species.

“These overlaps in function very plausibly contribute to numerous signals of selection being spread across different metabotropic receptor genes in distinct species.”

Glutamatergic signaling can control the release of serotonin from the dorsal raphe nucleus.

“glutamatergic signaling can also control the release of serotonin from the dorsal raphe nucleus (Celada et al., 2001).”

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The diversity of roles played by kainate receptors in the CNS, including extensive excitatory, inhibitory, ionotropic, and metabotropic activities, provides a wide range of possible functions upon which natural selection can act.

“The diversity of roles played by kainate receptors in the CNS, including extensive excitatory, inhibitory, ionotropic, and metabotropic activities (Contractor et al., 2011), provides a wide range of possible functions upon which natural selection can act.”

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Domestication of the pig appears to have involved important changes across both serotonergic and glutamatergic systems.

“Similarly, domestication of the pig appears to have involved important changes across both systems (Leno-Colorado et al., 2017).”

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Groups II and III metabotropic receptor subunits can have opposing actions within a single brain region that can vary according to the stressful stimuli being processed.

“Groups II and III metabotropic receptor subunits can have opposing actions within a single brain region that can vary according to the stressful stimuli being processed.”

At this point, the evidence from selective sweep studies strongly points to the involvement of glutamatergic signaling in domestication.

“At this point, the evidence from selective sweep studies strongly points to the involvement of glutamatergic signaling in domestication.”

• AssumptionRests on an assumption: The domesticated species and modern humans compared in the analysis have homologous stress-response brain regions and comparable glutamatergic signaling such that signals of selection can be meaningfully compared.

Even within receptor families, specific subunits and combinations of them or splice variants can have diametrically opposing functional properties from others that are nominally similar.

“Even within receptor families, specific subunits (and combinations of them) or splice variants can have diametrically opposing functional properties from others that are nominally similar (Bettler and Mulle, 1995;Perrais et al., 2010).”

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Glutamate mediates the release of oxytocin and vasopressin from the SON and PVN.

“Glutamate mediates the release of oxytocin and vasopressin from the SON and PVN (Busnardo et al., 2012).”

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Selective pressures seem to have honed varied specializations for kainate receptors in different brain regions.

“Selective pressures seem to have honed varied specializations for kainate receptors in different brain regions.”

Each receptor subfamily acts, broadly, to dampen stress responses.

“Each receptor subfamily acts, broadly, to dampen stress responses.”

Groups II and III metabotropic receptor subunits often have complementary functions within their subfamilies.

“This suggests that these subunits often have complementary functions within their subfamilies.”

Signals of selection associated with serotonergic signaling have been identified in a tame strain of rat and the domesticated goat.

“Signals of selection associated with serotonergic signaling have also been identified in a tame strain of rat and the domesticated goat (Albert et al., 2011;Dong et al., 2015).”

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• cites Dong et al., 2015 sourceNot checked yet

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Selective pressures, leaving genomic and neurobiological markers of convergence on kainate and Group II/III metabotropic receptor genes in humans and domesticated species, have led to downregulation of net excitatory inputs to the HPA axis and attenuation of the stress response.

“We have argued here that selective pressures, leaving genomic and neurobiological markers of convergence on kainate and Group II/III metabotropic receptor genes in ours and domesticated species, have led to downregulation of net excitatory inputs to the HPA axis and attenuation of the stress response.”

• AssumptionRests on an assumption: The domesticated species and modern humans compared in the analysis have homologous stress-response brain regions and comparable glutamatergic signaling such that signals of selection can be meaningfully compared.
• AssumptionRests on an assumption: Selection for tameness is the unifying domesticated trait.

Some evidence for direct effects of glutamate signaling derives from the fact that glutamate receptor, transporter, and other signaling genes identified in different domestication studies are expressed in melanocytes, osteoblasts, osteoclasts, chondrocytes, and other tissues beyond the CNS.

“Some evidence for this derives from the fact that glutamate receptor, transporter, and other signaling genes identified in different domestication studies are expressed in melanocytes, osteoblasts, osteoclasts, chondrocytes, and other tissues beyond the CNS (Wang et al., 2005;Hoogduijn et al., 2006;Devi et al., 2013;Julio-Pieper et al., 2011;Matta, 2013).”

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• cites Hoogduijn et al., 2006 sourceNot checked yet

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• cites Devi et al., 2013 sourceNot checked yet

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In cell cultures, glucocorticoids are essential for NCC survival and differentiation.

“In cell cultures, glucocorticoids are essential for NCC survival and differentiation (Doupe et al., 1985).”

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NMDA receptors have been implicated in the maturation and differentiation of chondrocytes.

“NMDA receptors have been implicated in the maturation and differentiation of chondrocytes (Takahata et al., 2008).”

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Glucocorticoid levels are lower during gestation in both tame rats and foxes compared with aggressive strains.

“glucocorticoid levels are lower during gestation in both tame rats and foxes compared with aggressive strains (Oskina et al., 2010).”

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The above studies suggest that lowered stress hormone levels in the womb, resulting from HPA hypofunction in the mother, can have the knock-on effect of bringing about neural crest hypofunction and cell-differentiation changes in embryonic development.

“The above studies suggest that lowered stress hormone levels in the womb, resulting from HPA hypofunction in the mother can have the knock-on effect of bringing about neural crest hypofunction and celldifferentiation changes in embryonic development.”

This suggests that at least some of the most important phenotypical features of domestication need not depend on genetic changes to NCC development or migration, but rather on postmigratory regulation of expression at different tissue sites by glucocorticoids.

“This suggests that at least some of the most important phenotypical features of domestication need not depend on genetic changes to NCC development or migration, but, rather, on postmigratory regulation of expression at different tissue sites by glucocorticoids.”

GRIK5, GRM4, and GRM8 along with NMDA and AMPA receptor genes are expressed in vitro in developing rat calvarial osteoblasts.

“GRIK5, GRM4, and GRM8 along with NMDA and AMPA receptor genes are expressed in vitro in developing rat calvarial osteoblasts (Hinoi et al., 2001(Hinoi et al., , 2002)).”

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In both the rat and duck studies, the effects of glucocorticoids on embryonic development take place long after neurulation and migration of neural crest cells away from the neural tube.

“In both the rat and duck studies, the effects of glucocorticoids on embryonic development take place long after neurulation and migration of neural crest cells away from the neural tube.”

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• cites Martin, 1975Not checked yet

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• cites Martin, 1978Not checked yet

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Removal of corticosteroids and replacement with nerve growth factor converts small intensely fluorescent cells and chromaffin cells into sympathetic neurons.

“Removal of corticosteroids and replacement with nerve growth factor converts small intensely fluorescent cells and chromaffin cells into sympathetic neurons (Doupe et al., 1985a(Doupe et al., , 1985b)).”

• cites Doupe et al., 1985aNot checked yet

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• cites Doupe et al., 1985bNot checked yet

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Traits such as floppy ears, shortened snouts, or depigmentation could feasibly result from alterations to glutamatergic receptor expression in tissues beyond the CNS.

“Thus, traits such as floppy ears, shortened snouts, or depigmentation could feasibly result from alterations to glutamatergic receptor expression in these tissues.”

• AssumptionRests on an assumption: The suite of phenotypic changes that make up the domestication syndrome, including tameness and physical traits such as floppy ears, shortened snouts, and depigmentation, is a valid unified phenomenon.