Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism

Burket, Jessica A.; Benson, Andrew D.; Green, Torrian L.; Rook, Jerri M.; Lindsley, Craig W.; Conn, P. Jeffrey; Deutsch, Stephen I.

doi:10.1016/j.pnpbp.2015.03.003

Cited by 18 publications

(13 citation statements)

References 35 publications

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“…Importantly, our data presented here suggest that GlyT1 inhibitors represent a class of drugs with the potential to reduce the seizure burden in chronic epilepsy. Since GlyT1 antagonists have proven pro-cognitive activities in models of schizophrenia, autism, and Alzheimer’s disease (Burket et al, 2015; Chaki et al, 2015; Harada et al, 2012), GlyT1 inhibitors would differ from conventional antiepileptic drugs, which generally impede cognitive function (Arif et al, 2009; Ortinski and Meador, 2004; Vajda, 2007). While we currently do not propose to use GlyT1 inhibitors in lieu of conventional epilepsy therapy, the new agents, in particular at lower doses, might yield highly desirable outcome as add-on to existing treatments.…”

Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Glycine transporter 1 is a target for the treatment of epilepsy

et al. 2015

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“…Increasing the NMDA receptor function by both acute and sub-chronic administration of TASP0315003 was shown to reverse PCP-induced deficits in social interaction, without altering social investigation in control mice [101]. Another selective high-affinity competitive GlyT1 inhibitor, 2,4-dichloro-N-((4-(cyclopropylmethyl)-1-(ethyl sulfonyl)piperidin-4-yl)methyl)benzamide (VU0410120), improved the social interaction deficits of autistic Balb/c mice [102], further demonstrating the efficacy of GlyT1 inhibitors.…”

Section: Role Of the Nmda Receptors In Social Interactionmentioning

confidence: 99%

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

Zoicas

Kornhuber

2019

IJMS

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The appropriate display of social behaviors is essential for the well-being, reproductive success and survival of an individual. Deficits in social behavior are associated with impaired N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. In this review, we describe recent studies using genetically modified mice and pharmacological approaches which link the impaired functioning of the NMDA receptors, especially of the receptor subunits GluN1, GluN2A and GluN2B, to abnormal social behavior. This abnormal social behavior is expressed as impaired social interaction and communication, deficits in social memory, deficits in sexual and maternal behavior, as well as abnormal or heightened aggression. We also describe the positive effects of pharmacological stimulation of the NMDA receptors on these social deficits. Indeed, pharmacological stimulation of the glycine-binding site either by direct stimulation or by elevating the synaptic glycine levels represents a promising strategy for the normalization of genetically-induced, pharmacologically-induced or innate deficits in social behavior. We emphasize on the importance of future studies investigating the role of subunit-selective NMDA receptor ligands on different types of social behavior to provide a better understanding of the underlying mechanisms, which might support the development of selective tools for the optimized treatment of disorders associated with social deficits.

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“…Standardized procedures exist to characterize deficits in social preference, social exploration and social memory in mice serving as models of ASD [21]. Ultimately, pharmacotherapeutic strategies that address etiopathogenic mechanisms, as opposed to prominent symptoms domains, must be found for this family of neurodevelopmental disorders [22][23][24][25][26]. Unfortunately, interventions directed at underlying etiologies and mechanisms of pathogenesis do not currently exist.…”

Section: Discussionmentioning

confidence: 99%