The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

Zoicas, Iulia; Kornhuber, Johannes

doi:10.3390/ijms20225599

Cited by 22 publications

(12 citation statements)

References 186 publications

(244 reference statements)

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“…Taken together, our results are in striking alignment with previous evidence indicating that alterations of glutamate neurotransmission mediated by NMDA receptors in the PFC play a critical role in the expression of maladaptive behavioral responses, including pathological aggression, behavioral flexibility, and cognitive deficits [23,[26][27][28]. In the PFC, NMDA receptors are abundantly expressed both on GABAergic interneurons and glutamatergic pyramidal cells.…”

Section: Discussionsupporting

confidence: 91%

Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice

et al. 2022

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The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT2 and glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Indeed, blocking either receptor reduces the aggression of MAOA knockout (KO) mice; however, 5-HT2 receptor antagonists, such as ketanserin (KET), reduce locomotor activity, while NMDA receptor blockers are typically associated with psychotomimetic properties. To verify whether NMDA receptor blockers induce psychotomimetic effects in MAOA KO mice, here we tested the effects of these compounds on prepulse inhibition (PPI) of the acoustic startle reflex. We found that male MAOA KO mice are hypersensitive to the PPI-disrupting properties of NMDA receptor antagonists, including the non-competitive antagonist dizocilpine (DIZ; 0.1, 0.3 mg/kg, IP) and the NR2B subunit-specific blocker Ro-256981 (5, 10 mg/kg, IP). Since KET has been previously shown to counter the PPI deficits caused by NMDA receptor antagonists, we tested the behavioral effects of the combination of KET (2 mg/kg, IP) and these drugs. Our results show that the combination of KET and DIZ potently reduces aggression in MAOA KO mice without any PPI deficits and sedative effects. While the PPI-ameliorative properties of KET were also observed after infusion in the medial PFC (0.05 μg/side), KET did not counter the PPI-disruptive effects of Ro-256981 in MAOA KO mice. Taken together, these results point to the combination of non-subunit-selective NMDA and 5-HT2 receptor antagonists as a potential therapeutic approach for aggression and antisocial behavior with a better safety and tolerability profile than each monotherapy.

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Section: Discussionsupporting

confidence: 91%

Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice

et al. 2022

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“…Consistent with a positive effect of 24S-hydroxycholesterol on NMDAR activity and cognitive function, increased cerebral 24S-hydroxycholesterol levels improve spatial memory function in mice 111,112 , whereas reduced levels cause impaired learning and memory function 113,114 . NMDAR activity also exerts a strong influence on social behavior, as NMDAR agonists improve social behavior in rodents, whereas antagonists impair it 115 .…”

Section: Loss Of Cyp39a1 and Advanced Social Behaviormentioning

confidence: 99%

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding

Blumer

Brown

Freitas

et al. 2021

Preprint

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Feeding exclusively on blood, vampire bats represent the only obligate sanguivorous lineage among mammals. To uncover genomic changes associated with adaptations to this unique dietary specialization, we generated a new haplotype-resolved reference-quality genome of the common vampire bat (Desmodus rotundus) and screened 26 bat species for genes that were specifically lost in the vampire bat lineage. We discovered previously-unknown gene losses that relate to metabolic and physiological changes, such as reduced insulin secretion (FFAR1, SLC30A8), limited glycogen stores (PPP1R3E), and a distinct gastric physiology (CTSE). Other gene losses likely reflect the biased nutrient composition (ERN2, CTRL) and distinct pathogen diversity of blood (RNASE7). Interestingly, the loss of REP15 likely helped vampire bats to adapt to high dietary iron levels by enhancing iron excretion and the loss of the 24S-hydroxycholesterol metabolizing enzyme CYP39A1 could contribute to their exceptional cognitive abilities. Finally, losses of key cone phototransduction genes (PDE6H, PDE6C) suggest that these strictly-nocturnal bats completely lack cone-based vision. These findings enhance our understanding of vampire bat biology and the genomic underpinnings of adaptations to sanguivory.

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“…Particularly, despite the importance of PSD-95 in synaptic function and the notorious impairment of synaptic dysconnectivity seen in both SCZ and ASD (Tsatsanis et al, 2003 ; Nair et al, 2013 ; Buchmann et al, 2014 ), it remains unknown whether PSD-95 deficiency would also affect synaptic function and connectivity in the mPFC. NMDA receptors are essential for the social brain (Ferri et al, 2020 ) and social behavior development in rodents (Zoicas and Kornhuber, 2019 ). Activation of NMDARs regulates sociability (Burket et al, 2015 ), and NMDAR dysfunction is a prominent pathophysiological feature in ASD (Won et al, 2012 ; Coley and Gao, 2018 ; Chung et al, 2019 ).…”

mentioning

confidence: 99%

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

Gao

Mack

2021

Front. Behav. Neurosci.

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Abnormal social behavior, including both hypo- and hypersociability, is often observed in neurodevelopmental disorders such as autism spectrum disorders. However, the mechanisms associated with these two distinct social behavior abnormalities remain unknown. Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein in the excitatory synapses and an essential regulator of synaptic maturation by binding to NMDA and AMPA receptors. The DLG4 gene encodes PSD-95, and it is a risk gene for hypersocial behavior. Interestingly, PSD-95 knockout mice exhibit hyposociability during adolescence but hypersociability in adulthood. The adolescent hyposociability is accompanied with an NMDAR hyperfunction in the medial prefrontal cortex (mPFC), an essential part of the social brain for control of sociability. The maturation of mPFC development is delayed until young adults. However, how PSD-95 deficiency affects the functional maturation of mPFC and its connection with other social brain regions remains uncharacterized. It is especially unknown how PSD-95 knockout drives the switch of social behavior from hypo- to hyper-sociability during adolescent-to-adult development. We propose an NMDAR-dependent developmental switch of hypo- to hyper-sociability. PSD-95 deficiency disrupts NMDAR-mediated synaptic connectivity of mPFC and social brain during development in an age- and pathway-specific manner. By utilizing the PSD-95 deficiency mouse, the mechanisms contributing to both hypo- and hyper-sociability can be studied in the same model. This will allow us to assess both local and long-range connectivity of mPFC and examine how they are involved in the distinct impairments in social behavior and how changes in these connections may mature over time.

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The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

Cited by 22 publications

References 186 publications

Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice

Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice

Gene losses in the common vampire bat illuminate molecular adaptations to blood feeding

From Hyposociability to Hypersociability—The Effects of PSD-95 Deficiency on the Dysfunctional Development of Social Behavior

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