NMDA Receptor Complex Research Articles

DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease.

Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Disrupted cortico-striatal transmission is an early event that contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons, the most vulnerable cell type in the disease, but also in neurons of other brain regions including the cortex. Although striatal and cortical neurons eventually degenerate, these synaptic and circuit changes may underlie some of the earliest motor, cognitive, and psychiatric symptoms. Moreover, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs, and restoration of normal synaptic function may delay neurodegeneration. One of the earliest synaptic alterations to occur in HD mouse models is enhanced striatal extrasynaptic NMDA receptor expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is associated with increased activation of cell death pathways, inhibition of survival signaling, and greater susceptibility to excitotoxicity. Death-associated protein kinase 1 (DAPK1) is a pro-apoptotic kinase highly expressed in neurons during development. In the adult brain, DAPK1 becomes re-activated and recruited to extrasynaptic NMDAR complexes during neuronal death, where it phosphorylates GluN2B at S1303, amplifying toxic receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer’s disease, Parkinson’s disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. Here, we demonstrate that dysregulation of DAPK1 occurs early in the YAC128 HD mouse model, and contributes to elevated extrasynaptic GluN2B S1303 phosphorylation. Inhibition of DAPK1 normalizes extrasynaptic GluN2B phosphorylation and surface expression, and completely prevents YAC128 striatal spine loss in cortico-striatal co-culture, thus validating DAPK1 as a potential target for synaptic protection in HD and warranting further development of DAPK1-targeted therapies for neurodegeneration.

Cloning and characterisation of NMDA receptors in the Pacific oyster, Crassostrea gigas (Thunberg, 1793) in relation to metamorphosis and catecholamine synthesis

Bivalve metamorphosis is a developmental transition from a free-living larva to a benthic juvenile (spat), regulated by a complex interaction of neurotransmitters and neurohormones such as L-DOPA and epinephrine (catecholamine). We recently suggested an N-Methyl-D-aspartate (NMDA) receptor pathway as an additional and previously unknown regulator of bivalve metamorphosis. To explore this theory further, we successfully induced metamorphosis in the Pacific oyster, Crassostrea gigas, by exposing competent larvae to L-DOPA, epinephrine, MK-801 and ifenprodil. Subsequently, we cloned three NMDA receptor subunits CgNR1, CgNR2A and CgNR2B, with sequence analysis suggesting successful assembly of functional NMDA receptor complexes and binding to natural occurring agonists and the channel blocker MK-801. NMDA receptor subunits are expressed in competent larvae, during metamorphosis and in spat, but this expression is neither self-regulated nor regulated by catecholamines. In-situ hybridisation of CgNR1 in competent larvae identified NMDA receptor presence in the apical organ/cerebral ganglia area with a potential sensory function, and in the nervous network of the foot indicating an additional putative muscle regulatory function. Furthermore, phylogenetic analyses identified molluscan-specific gene expansions of key enzymes involved in catecholamine biosynthesis. However, exposure to MK-801 did not alter the expression of selected key enzymes, suggesting that NMDA receptors do not regulate the biosynthesis of catecholamines via gene expression.

Pharmacological Screening of Mangifera indica Seeds for Antidepressant-like Action Along with a Mechanistic Study.

Depression is emerging as a major global issue. There are several antidepressants available in the market, but their efficacy is usually unpredictable. Therefore, there is a need to find an alternative therapeutic agent with better therapeutic efficacy and availability. In the current investigation, the antidepressant-like action of the aqueous methanolic extract of Mangifera indica seeds (25, 50, and 100 mg/kg) was evaluated by two predictive models like the tail suspension test and forced swimming test along with the determination of the mechanism of action working behind this action. The results of the acute treatment with the extract show a dose-dependent reduction in the duration of immobility in both models. The antidepressant-like action of the extract (100 mg/kg) was blocked by the administration of p-chlorophenyl alanine, α-methyl-p-tyrosine, prazosin, and sulpiride while remaining unaffected with propranolol. In contrast, the administration of d-serine along with the extract (a full agonist of glycine/N-methyl-d-aspartate, NMDA, receptors) diminished the anti-immobility action. The administration of the extract along with nitro-l-arginine-methyl ester synergizes into the anti-immobility action of the extract, and intake of l-arginine remained unable to effect this action, whereas sildenafil blocks the effect. The antidepressant-like action of the extract is probably due to the involvement of serotonergic and adrenergic (mainly α receptors are involved) systems, an NMDA receptor complex, and the nitric oxide pathway.

Studying the anticonvulsive activity of new ligands of NDMA-receptor complex – imidazole-4,5-dicarbonic acid derivatives

NMDA receptors were proven to play a significant role in the processes of epileptogenesis. Experimental data indicate a significant anticonvulsant effect of NMDA receptor antagonists, but the use of the studied NMDA ligands remains limited due to their low efficiency and toxic effects. The aim of the study was to investigate the anticonvulsant effect of new ligands of the glutamate NMDA receptor complex imidazole-4,5-dicarboxylic acid (IDA) derivatives on a model of NMDA-induced convulsions in mice. The tested agents (IEM2258 and IEM2248) were injected into the lateral ventricles of a waking mouse brain at doses of 0.10.5 mmol in 5 l 15 minutes before the convulsant (NMDA). Valproic acid was used as a comparator drug. The results of the study showed that IDA derivatives exhibit anticonvulsant activity of various degrees of severity. A pronounced anticonvulsant effect was established for IEM2258 at a dose of 0.4 mmol: a significant reduction in the duration of convulsions (compared to the previous dose of the tested substance) and a total absence of NMDA-induced deaths. IEM2248 showed anticonvulsant activity at a dose of 0.2 mmol, in 100% of cases preventing fatal outcomes and completely protecting animals from the convulsions. Thus, the data obtained in this study showed dose-dependent anticonvulsant effect of new IDA derivatives (IEM2258 and IEM2248) due to the blockade of the NMDA receptor complex, that indicates the promising aspect for the development of these agents and further searching for effective and safe anticonvulsants among this pharmacological class.

SULT4A1 Modulates Synaptic Development and Function by Promoting the Formation of PSD-95/NMDAR Complex.

Sulfotransferase 4A1 (SULT4A1) is a cytosolic sulfotransferase that is highly conserved across species and extensively expressed in the brain. However, the biological function of SULT4A1 is unclear. SULT4A1 has been implicated in several neuropsychiatric disorders, such as Phelan-McDermid syndrome and schizophrenia. Here, we investigate the role of SULT4A1 within neuron development and function. Our data demonstrate that SULT4A1 modulates neuronal branching complexity and dendritic spines formation. Moreover, we show that SULT4A1, by negatively regulating the catalytic activity of Pin1 toward PSD-95, facilitates NMDAR synaptic expression and function. Finally, we demonstrate that the pharmacological inhibition of Pin1 reverses the pathologic phenotypes of neurons knocked down by SULT4A1 by specifically restoring dendritic spine density and rescuing NMDAR-mediated synaptic transmission. Together, these findings identify SULT4A1 as a novel player in neuron development and function by modulating dendritic morphology and synaptic activity.SIGNIFICANCE STATEMENT Sulfotransferase 4A1 (SULT4A1) is a brain-specific sulfotransferase highly expressed in neurons. Different evidence has suggested that SULT4A1 has an important role in neuronal function and that SULT4A1 altered expression might represent a contributing factor in multiple neurodevelopmental disorders. However, the function of SULT4A1 in the mammalian brain is still unclear. Here, we demonstrate that SULT4A1 is highly expressed at postsynaptic sites where it sequesters Pin1, preventing its negative action on synaptic transmission. This study reveals a novel role of SULT4A1 in the modulation of NMDA receptor activity and strongly contributes to explaining the neuronal dysfunction observed in patients carrying deletions of SULTA41 gene.

Evaluation of 11C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats.

[S-methyl-11C](±)-7-methoxy-3-(4-(4-(methylthio)phenyl)butyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-ol (11C-NR2B-SMe) and its enantiomers were synthesized as candidates for imaging the NR2B subunit within the N-methyl-d-aspartate receptor with PET. Methods: Brains were scanned with PET for 90 min after intravenous injection of one of the candidate radioligands into rats. To detect any NR2B-specific binding of radioligand in brain, various preblocking or displacing agents were evaluated for their impact on the PET brain imaging data. Radiometabolites from brain and other tissues were measured ex vivo and in vitro. Results: Each radioligand gave high early whole-brain uptake of radioactivity, followed by a brief fast decline and then a slow final decline. 11C-(S)-NR2B-SMe was studied extensively. Ex vivo measurements showed that radioactivity in rat brain at 30 min after radioligand injection was virtually unchanged radioligand. Only less lipophilic radiometabolites appeared in plasma. High-affinity NR2B ligands, Ro-25-6981, ifenprodil, and CO101244, showed increasing preblocking of whole-brain radioactivity retention with increasing dose (0.01-3.00 mg/kg, intravenously). Five σ1 antagonists (FTC146, BD1407, F3, F4, and NE100) and 4 σ1 agonists ((+)-pentazocine, (±)-PPCC, PRE-084, and (+)-SKF10047) were ineffective preblocking agents, except FTC146 and F4 at a high dose. Two potent σ1 receptor agonists, TC1 and SA4503, showed dose-dependent preblocking effects in the presence or absence of pharmacologic σ1 receptor blockade with FTC146. Conclusion:11C-(S)-NR2B-SMe has adequate NR2B-specific PET signal in rat brain to warrant further evaluation in higher species. TC1 and SA4503 likely have off-target binding to NR2B in vivo.

Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function.

Efforts to develop efficacious antidepressant agents with novel mechanisms have largely unsuccessful since the 1950’s until the discovery of ketamine, an NMDA receptor antagonist that produces rapid and sustained antidepressant actions even in treatment resistant patients. This finding has ushered a new era for the development of novel rapid acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here we review the current state of rapid acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and increased synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.

Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease

Much evidence suggests that hypofunction of the N-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways. We recently showed reduced Src signaling in post mortem tissue from schizophrenia patients, despite increased MK-801 binding and NMDA receptor complex expression in the postsynaptic density (PSD). These data suggest that Src dysregulation may be an important underlying mechanism responsible for reduced glutamate signaling. Despite this evidence for a central role of Src in NMDAR signaling, little is known about how reductions in Src activity might regulate phenotypic changes in cognition and behavior. As such, the current study sought to characterize behavioral and electrophysiological phenotypes in mice heterozygous for the Src Acl gene (Src+/− mice). Src+/− mice demonstrated decreased sociability and working memory relative to Src+/+ (WT) mice while no significant differences were seen on locomotive activity and anxiety-related behavior. In relation to WT mice, Src+/− mice showed decreased mid-latency P20 auditory event related potential (aERP) amplitudes, decreased mismatch negativity (MMN) and decreased evoked gamma power, which was only present in males. These data indicate that Src+/− mice are a promising new model to help understand the pathophysiology of these electrophysiological, behavioral and cognitive changes. As such, we propose that Src+/− mice can be used in the future to evaluate potential therapeutic approaches by targeting increased Src activity as a common final pathway for multiple etiologies of SCZ and other diseases characterized by reduced glutamate function.

SA99 - TARGETED SEQUENCING OF 187 PUTATIVE SCHIZOPHRENIA RISK GENES IN 5,207 CASES AND 4,991 CONTROLS

Background Recent sequencing studies have shown a small fraction of SZ risk comes from rare mutations. They have also advanced our understanding of SZ pathophysiology, with multiple studies implicating post-synaptic proteins, including the activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Thus far, only one gene, SETD1A, has been associated with SZ at genome-wide levels of significance. We aimed to identify novel SZ genes by sequencing 187 genes in 5,207 cases and 4,991 controls. Included among these genes are members of ARC and NMDAR complexes, as well as Voltage-Gated Sodium (VGSC) and Calcium Channels (VGCC), all of which have been previously implicated in SZ. Methods A total of 5,724 cases, 5,769 controls were selected for Ion Torrent sequencing of 187 candidate SZ genes. None of these samples have been included in previous SZ sequencing studies. After stringent quality control (low sequence quality, relatedness and ancestry), our sample consisted 5,207 cases and 4,991 controls. Gene-set and single-gene association statistics were generated using a Firth's penalised-likelihood logistic regression model. Results Cases had a significant excess of Loss-of-Function (LoF) mutations ( Discussion In a new, independent sequencing study of SZ, we found an excess of LoF alleles in cases in all 187 targeted genes, and provide independent support for the involvement of ARC and NMDAR post-synaptic protein complexes, and voltage-gated sodium channels, in SZ pathogenesis. We also provide further evidence for a shared genetic risk between SZ and DD. However, our study was underpowered to identify specific risk genes.

EXPERIMENTAL MODEL OF SCHIZOPHRENIA AND MORPHOLOGICAL CHANGES IN BRAIN

Schizophrenia is a complex psychiatric mental disorder often characterized by abnormal social behavior and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, auditory hallucinations, reduced social engagement and emotional expression, and inactivity. Neuroontogenetic theory explains the occurrence of disease events taken place during intrauterine period. Gutamatergic signaling interferes with ethion-pathogenic mechanisms of schizophrenia. The disease is associated with N-methyl-D-aspartate NMDA receptor hypofunction and a number of genes suspected in respect of schizophrenia influence on a NMDA receptor signaling. NRG1 and ErbB4 its receptor involved in the glutamatergic signaling by regulating the NMDA receptor complex. Neuregulins are signaling proteins structurally related to the epidermal growth factor (EGF). The mechanisms underlying the contribution of NRG1/ErbB4 system to schizophrenia pathophysiology remain insignificant, but they reveal only after the complete maturation of the brain. Prenatal stress in rats simulates many of the cognitive and sensory deficits manifest in the disease. Identified in this experimental model deficits in immunochistochemical expression of Neuroregulin1- ErbB4- system directed changes at the molecular level in the hippocampus, a brain structure with a role in the regulation of stress.

Higher Levels of Protein Palmitoylation in the Frontal Cortex across Aging Were Associated with Reference Memory and Executive Function Declines.

Cognitive decline with aging is often due to altered levels of protein expression. The NMDA receptor (NMDAR) and the complex of proteins surrounding the receptor are susceptible to age-related changes in expression. In the frontal cortex of aged mice, there is a significant loss of expression of the GluN2B subunit of the NMDAR, an increase in Fyn expression, and no change in PSD-95. Studies have also found that, in the frontal cortex, phosphorylation of GluN2B subunits and palmitoylation of GluN2 subunits and NMDAR complex proteins are affected by age. In this study, we examined some of the factors that may lead to the differences in the palmitoylation levels of NMDAR complex proteins in the frontal cortex of aged animals. The Morris water maze was used to test spatial learning in 3- and 24-month-old mice. The acyl–biotinyl exchange method was used to precipitate palmitoylated proteins from the frontal cortices and hippocampi of the mice. Additionally, brain lysates from old and young mice were probed for the expression of fatty acid transporter proteins. An age-related increase of palmitoylated GluN2A, GluN2B, Fyn, PSD-95, and APT1 (acyl protein thioesterase 1) in the frontal cortex was associated with poorer reference memory and/or executive functions. These data suggest that there may be a perturbation in the palmitoylation cycle in the frontal cortex of aged mice that contributes to age-related cognitive declines.

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca2+/CaMKII signaling.

The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD-95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how β2 adrenergic receptor (β2 AR) signaling via adenylyl cyclase and the cAMP-dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of β2 AR, adenylyl cyclase, and PKA to defined signaling complexes at postsynaptic sites, i.e., AMPARs and the L-type Ca2+ channel Cav1.2, and other subcellular surface localizations, the role of Akinase anchor proteins, the physiological relevance of the spatial restriction of corresponding signaling, and their interplay with signal transduction by the Ca2+- and calmodulin-dependent kinase CaMKII How localized and specific signaling by cAMP occurs is a central cellular question. The dendritic spine constitutes an ideal paradigm for elucidating the dimensions of spatially restricted signaling because of their small size and defined protein composition.

Modelling the details: integrating structure with function.

Modelling the details: integrating structure with function.

Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies

The ‘neurotrophic sesquiterpenes’ refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other ‘cage convulsant’ compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.

N-(5-Hydroxynicotinoil)-L-Glutamic Acid Calcium Salt Modifies Responses of Rat Hippocampal CA1 Pyramidal Neurons during Orthodromic Stimulation.

The study examined the effect of calcium salt of N-(5-hydroxynicotinoil)-L-glutamic acid (Ampasse preparation) on neuronal activity in hippocampal CA1 area evoked by stimulation of Schaffer collaterals at a rate of 1 Hz (30 impulses during 30 sec) in the surviving hippocampal slices of Wistar rats. The records of 1st and 30th orthodromic population spikes showed that Ampasse in concentrations of 500 μM, 1, 2, and 10 mM facilitated the synaptic transmission in Schaffer collaterals - hippocampal CA1 pyramidal neurons axis; the maximum effect was observed at 2 mM Ampasse. When used in a concentration of 10 mM, Ampasse provoked epileptiform activity, which could be prevented by MK-801, a specific noncompetitive antagonist of the NMDA-receptor complex.

Glutamate heteroreceptor complexes in the brain.

The existence of mGluR, NMDAR, AMPAR and putative KAR heteroreceptor complexes in synaptic and extrasynaptic regions of brain glutamate synapses represents a major integrative mechanism. Our aim in the current article is to analyze if the formation of the different types glutamate hetereceptor complexes involves the contribution of triplet amino acid homologies (protriplets) in a postulated receptor interface based on the triplet puzzle theory. Seven main sets (lists) of receptor pairs in databases were used containing various sets (lists) of human receptor heteromers and nonheteromers obtained from the available scientific publications including the publically available GPCR-hetnet database. Brain mGluR1-mGluR5 and mGluR2-mGluR4 isoreceptor complexes were demonstrated with a predominant extrasynaptic localization at a post- and prejunctional localization. The existence of putative mGluR4-mGluR7 heteroreceptor complexes in the basal ganglia is proposed. Metabotropic glutamate receptor subtypes also participated in the formation of a large number of heteroreceptor complexes like mGluR1-A1R, mGluR5-A2AR, mGluR5-D2R and D2R-A2AR-mGluR5, located in relation to glutamate synapses, especially in the basal ganglia. A putative mGluR1-GABAB1/2 heterocomplex may also exist. NMDAR heteroreceptor complexes were also demonstrated as a fundamental integrative mechanism in the glutamate synapse and its extrasynaptic membranes. It represented fundamental work on inter alia NMDAR-mGluR5, NMDAR-D1R and NMDAR-D2R heteroreceptor complexes involving both antagonistic and facilitatory allosteric receptor-receptor interactions. As to AMPA receptors, a heterocomplex was found for the interaction between IFNgR1 and the AMPAR mediated via the subunit GluA1 which may be of relevance for neuroinflammation. AMPAR-D2R heteroreceptor complexes were also demonstrated. Besides glutamate heteroreceptor complexes and their allosteric receptor-receptor interactions, a significant mechanism for the functional crosstalk can also be phosphorylation and/or reorganization of adapter proteins with dynamic binding to the two receptors modulating the allosteric receptor mechanism.

α2δ‐1 Is Essential for Angiotensin II‐Induced Sympathoexcitation and NMDA Receptor Hyperactivity in the Hypothalamus

Both the sympathetic nervous system and renin‐angiotensin system are critically involved in hypertension development. Although angiotensin II (Ang II) stimulates presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) to increase sympathetic vasomotor tone, the molecular mechanism responsible for this action remains unclear. The glutamate N‐methyl‐D‐aspartate receptor (NMDAR) in the PVN controls sympathetic outflow in hypertension. In this study, we determined how Ang II affects synaptic NMDARs in spinally projecting PVN neurons. Coimmunoprecipitation assays showed that α2δ‐1, commonly known as a voltage‐gated calcium channel subunit, interacted with the NMDAR in the hypothalamus of rats and humans. Ang II increased the synaptic expression level of α2δ‐1–NMDAR complexes. Also, Ang II increased pre‐ and postsynaptic NMDAR activity via AT1 receptors, and such effects were abolished either by treatment with pregabalin, an inhibitory α2δ‐1 ligand, or by interrupting the α2δ‐1–NMDAR interaction with α2δ‐1Tat peptide. In α2δ‐1 knockout mice, Ang II failed to affect the pre‐ and postsynaptic NMDAR activity of PVN neurons. In addition, the α2δ‐1Tat peptide blocked the sympathoexcitatory response to the microinjection of Ang II into the PVN. Our findings indicate that by promoting the synaptic trafficking of α2δ‐1–bound NMDARs, Ang II augments sympathetic vasomotor tone and excitatory glutamatergic input to PVN presympathetic neurons.Support or Funding InformationThis work was supported by the National Institutes of Health (Grant R01 HL131161) and the N.G. and Helen T. Hawkins Endowment (to H.‐L.P.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit

The N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of neurological diseases, such as schizophrenia, autism spectrum disorders (ASD), and Alzheimer's disease (AD), whose unique clinical hallmark is a constellation of impaired social and/or cognitive behaviors. GluN3A (NR3A) is a unique inhibitory subunit in the NMDAR complex. The role of GluN3A in social behavioral activities is obscure. In this study, we sought to evaluate altered social activities in adult GluN3A knockout (KO) mice. GluN3A KO mice spent less time in reciprocal social interaction in the social interaction test compared to wild-type (WT) mice. A social approach test using a three-chamber system confirmed that mice lacking GluN3A had lower sociability and did not exhibit a preference for social novelty. GluN3A KO mice displayed abnormal food preference in the social transmission of food preference task and low social interaction activity in the five-trial social memory test, but without social memory deficits. Using a home cage monitoring system, we observed reduced social grooming behavior in GluN3A KO mice. Signaling genes that might mediate the altered social behaviors were examined in the prefrontal cortex, hippocampus, and thalamus. Among nine genes examined, the expression of the oxytocin receptor was significantly lower in the prefrontal cortex of GluN3A KO mice than that in WT mice. Oxytocin treatment rescued social activity deficits in GluN3A KO mice. These findings support a novel idea that a chronic state of moderate increases in NMDAR activities may lead to downregulation of the oxytocin signaling and impaired behavioral activities that are seen in psychiatric/neurodegenerative disorders.

Positive and Negative Allosteric Modulators of N-Methyl-d-aspartate (NMDA) Receptors: Structure-Activity Relationships and Mechanisms of Action.

Excitatory activity in the CNS is predominately mediated by l-glutamate through several families of l-glutamate neurotransmitter receptors. Of these, the N-methyl-d-aspartate receptor (NMDAR) family has many critical roles in CNS function and in various neuropathological and psychiatric conditions. Until recently, the types of compounds available to regulate NMDAR function have been quite limited in terms of mechanism of action, subtype selectivity, and biological effect. However, several new classes of NMDAR agents have now been identified that are positive or negative allosteric modulators (PAMs and NAMs, respectively) with various patterns of NMDAR subtype selectivity. These new agents act at several newly recognized binding sites on the NMDAR complex and offer significantly greater pharmacological control over NMDAR activity than previously available agents. The purpose of this review is to summarize the structure-activity relationships for these new NMDAR modulator drug classes and to describe the current understanding of their mechanisms of action.

Genomic and Imaging Biomarkers in Schizophrenia.

Recent large-scale genomic studies have confirmed that schizophrenia is a polygenic syndrome and have implicated a number of biological pathways in its aetiology. Both common variants individually of small effect and rarer but more penetrant genetic variants have been shown to play a role in the pathogenesis of the disorder. No simple Mendelian forms of the condition have been identified, but progress has been made in stratifying risk on the basis of the polygenic burden of common variants individually of small effect, and the contribution of rarer variants of larger effect such as Copy Number Variants (CNVs). Pathway analysis of risk-associated variants has begun to identify specific biological processes implicated in risk for the disorder, including elements of the glutamatergic NMDA receptor complex and post synaptic density, voltage-gated calcium channels, targets of the Fragile X Mental Retardation Protein (FMRP targets) and immune pathways. Genetic studies have also been used to drive genomic imaging approaches to the investigation of brain markers associated with risk for the disorder. Genomic imaging approaches have been applied both to investigate the effect of polygenic risk and to study the impact of individual higher-penetrance variants such as CNVs. Both genomic and genomic imaging approaches offer potential for the stratification of patients and at-risk groups and the development of better biomarkers of risk and treatment response; however, further research is needed to integrate this work and realise the full potential of these approaches.