The NMDA Receptor and Schizophrenia

Balu, Darrick T.

doi:10.1016/bs.apha.2016.01.006

Cited by 242 publications

(130 citation statements)

References 156 publications

(195 reference statements)

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“…Spread throughout the central nervous system (7, 8), NMDARs are integral for fast excitatory signal transmission, essential for normal brain development, and function and are implicated in multiple neurological injuries, diseases and disorders (9). NMDARs play particularly crucial roles in learning and memory and are the targets of clinically relevant drugs for treatment of Alzheimer’s disease (10), schizophrenia (11), depression (12) and epilepsy (13). …”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Lü

Goehring

et al. 2017

Science

153

102

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Summary N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryo-EM. In the absence of Ro, the GluN2A and GluN2B amino terminal domains (ATD) adopt “closed” and “open” clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison to the GluN2B subunit. Differences in the conformation of the pseudo 2-fold related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity.

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Section: Introductionmentioning

confidence: 99%

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Lü

Goehring

et al. 2017

Science

153

102

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“…10,11 In addition, M 1 functionally interacts with the N -methyl-D-aspartate subtype of the glutamate receptor (NMDAR) 12 and has been shown to reverse behavioral pharmacological (phencyclidine and MK-801) and genetic (NR1 KD mice)NMDAreceptor deficits (i.e., the NMDA receptor hypofunction hypothesis of schizophrenia). 13–23 Over the last 30 years, the M 1 muscarinic acetylcholine receptor has emerged as an attractive molecular target for both of these devastating CNS disorders; however, while early efforts with orthosteric muscarinic agonists (activating M 1 –M 5 at varying degrees) showed a trend toward cognitive enhancing efficacy in patients, they failed to meet significant end points for cognition enhancement, a result attributed to dose-limiting nonselective cholinergic agonist adverse effects mediated by the concomitant activation of peripheral M 2 and M 3 receptors. 13–25 Similarly, functionally M 1 selective allosteric agonists garnered interest early on.…”

Section: Introductionmentioning

confidence: 99%

“…13–23 Over the last 30 years, the M 1 muscarinic acetylcholine receptor has emerged as an attractive molecular target for both of these devastating CNS disorders; however, while early efforts with orthosteric muscarinic agonists (activating M 1 –M 5 at varying degrees) showed a trend toward cognitive enhancing efficacy in patients, they failed to meet significant end points for cognition enhancement, a result attributed to dose-limiting nonselective cholinergic agonist adverse effects mediated by the concomitant activation of peripheral M 2 and M 3 receptors. 13–25 Similarly, functionally M 1 selective allosteric agonists garnered interest early on. However, many of these compounds proved to interact with both the orthosteric and allosteric binding sites of the receptor and bound bitopically to the receptor.…”

Section: Introductionmentioning

confidence: 99%

Diverse Effects on M₁ Signaling and Adverse Effect Liability within a Series of M₁ Ago-PAMs

Rook

Abe

Cho

et al. 2017

ACS Chem. Neurosci.

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Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer’s disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M1 ago-PAMs. Our data demonstrate that closely related M1 PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M1 PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M1 responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M1 PAMs.

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“…1–3 Previous studies have demonstrated that acute or chronic administration of noncompetitive NMDAR antagonists, including phencyclidine (PCP) and ketamine, induce psychotic-like symptoms and cognitive impairments in animals and healthy individuals and exacerbate symptoms in patients with schizophrenia (see reviews by refs 1,4). Recent copy number variation analysis studies have identified numerous de novo mutations in genes encoding the NMDAR and other proteins within the glutamatergic postsynaptic density associated with increased risk of schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…Recent development of several genetic models of reduced NMDAR activity have provided important in vivo systems for studying changes in relevant cortical and limbic circuitry comparable to those observed in schizophrenia (see refs 1,9–11,13,57,58). While the null mutation of G rin1 , the gene encoding the NR1 subunit of NMDARs, is lethal, a hypomorphic or partial loss-of-function mutation of G rin1 results in an NR1 subunit knockdown (NR1 KD) mouse that is still viable.…”

Section: Introductionmentioning

confidence: 99%

Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M₁ PAM VU6004256

Grannan

Mielnik

Moran

et al. 2016

ACS Chem. Neurosci.

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Abnormalities in the signaling of the N-methyl-D-aspartate subtype of the glutamate receptor (NMDAR) within cortical and limbic brain regions are thought to underlie many of the complex cognitive and affective symptoms observed in individuals with schizophrenia. The M1 muscarinic acetylcholine receptor (mAChR) subtype is a closely coupled signaling partner of the NMDAR. Accumulating evidence suggests that development of selective positive allosteric modulators (PAMs) of the M1 receptor represent an important treatment strategy for the potential normalization of disruptions in NMDAR signaling in patients with schizophrenia. In the present studies, we evaluated the effects of the novel and highly potent M1 PAM, VU6004256, in ameliorating selective prefrontal cortical (PFC)-mediated physiologic and cognitive abnormalities in a genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Using slice-based extracellular field potential recordings, deficits in muscarinic agonist-induced long-term depression (LTD) in layer V of the PFC in the NR1 KD mice were normalized with bath application of VU6004256. Systemic administration of VU6004256 also reduced excessive pyramidal neuron firing in layer V PFC neurons in awake, freely moving NR1 KD mice. Moreover, selective potentiation of M1 by VU6004256 reversed the performance impairments of NR1 KD mice observed in two preclinical models of PFC-mediated learning, specifically the novel object recognition and cue-mediated fear conditioning tasks. VU6004256 also produced a robust, dose-dependent reduction in the hyperlocomotor activity of NR1 KD mice. Taken together, the current findings provide further support for M1 PAMs as a novel therapeutic approach for the PFC-mediated impairments in schizophrenia.

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The NMDA Receptor and Schizophrenia

Cited by 242 publications

References 156 publications

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Diverse Effects on M₁ Signaling and Adverse Effect Liability within a Series of M₁ Ago-PAMs

Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M₁ PAM VU6004256

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The NMDA Receptor and Schizophrenia

Cited by 242 publications

References 156 publications

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs

Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256

Contact Info

Product

Resources

About

Diverse Effects on M₁ Signaling and Adverse Effect Liability within a Series of M₁ Ago-PAMs

Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M₁ PAM VU6004256