Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents

Deiana, Serena; Hauber, Wolfgang; Münster, Alexandra; Sommer, Susanne; Ferger, Boris; Marti, Anelise; Schmid, Bernhard; Dorner-Ciossek, Cornelia; Rosenbrock, Holger

doi:10.1016/j.ejphar.2022.175306

Cited by 10 publications

(8 citation statements)

References 61 publications

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“…Javitt et al [20,21]found that forebrain neuron-speci c GlyT1 de ciency was su cient to improve the performance of a variety of cognitive processes, including enhanced associative learning, Pavlovian conditioning, reversal learning, recognition of objects, and object location memory. The use of GlyT1 inhibitors can treat conditions that are characterized by low NMDR function, such as the cognitive symptoms of schizophrenia [22]. Unlike previous studies, our previous study showed that GlyT1 expression was downregulated in the hippocampal tissues of diabetic rats with cognitive dysfunction.…”

Section: Introductioncontrasting

confidence: 59%

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

Yang

Zhū

et al. 2023

Preprint

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Diabetes-associated cognitive dysfunction(DACD) is one of the neurological complications of diabetes, and it mainly involves the hippocampal region of the brain and affects the learning and memory functions of the body. There are many studies on the pathogenesis of DACD, but there is a lack of in-depth studies on the underlying molecular mechanism, which poses a great challenge to drug development. In this study, we focused on the molecular mechanism by which signal transduction by the glycine transporter GlyT1 participates in the development of DACD and systematically elucidated the processes of synaptic plasticity and apoptosis in hippocampal neurons. The results showed that when neurons were exposed to a high-glucose environment, low levels of GlyT1 inhibited the activation of the PI3K/AKT/mTOR pathway to promote neuronal apoptosis; additionally, GlyT1 regulated NMDR expression to regulate glycine concentrations in order to reduce synaptic plasticity. The transcription factor Sp1 bound to the GlyT1 promoter region and regulated GlyT1 expression, so we explored whether Sp1 expression was regulated by the protease-ubiquitin system, resulting in decreased Sp1 levels.In conclusion, In conclusion, our study systematically demonstrated the biological function and molecular mechanism by which GlyT1 participates in DACD development, elucidated the upstream and downstream mechanisms of GlyT1 regulation, provided reliable molecular targets for DACD treatment, and enhanced the understanding of the mechanism underlying DACD development.

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Section: Introductioncontrasting

confidence: 59%

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

Yang

Zhū

et al. 2023

Preprint

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“…Spontaneous alternation in T-Maze was performed as previously described (Deiana et al, 2022) in male C57BL/6JRj mice (17-19gr at arrival), treated either with saline or PCP (see Animals and drug treatment section above). In brief, mice were tested in a single T-maze session, which consisted of 1 forced and a maximum of 14 free-choice trials or 10 minutes spontaneous exploration, whichever occurred first.…”

Section: Methodsmentioning

confidence: 99%

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Ponserre,

Ionescu,

Franz

et al. 2024

Preprint

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Pharmacological approaches to induce N-methyl-D-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in mice that underwent a 7-day subchronic phencyclidine (PCP 10mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus (HPC) to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

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“…Furthermore, Drugs stimulating glutamatergic transmission through metabotropic receptors (e.g. mGluR2/3) or by increasing the synaptic concentration of NMDA receptor co-agonist glycine or Dserine improve symptoms of SZ including social interaction deficits in animal models and SZ patients (Harich et al, 2007, Shimazaki et al, 2010, Clifton et al, 2013, Chaki et al, 2015, Kantrowitz et al, 2016, 2019Hirayasu et al, 2016;Luesson et al, 2022& Deiana et al, 2022, thus establishing that NMDA receptor hypofunction is a factor contributing to social deficits in rodent models of SZ.…”

Section: Immune Dysregulation Is Associated With Social Cognition Imp...mentioning

confidence: 99%

“…In addition, pharmacological modulators of the glutamatergic transmission should also be considered. For example, metabotropic glutamate receptor modulators and compounds modulating the synaptic concentration of NMDA receptor co-agonists glycine and D-serine show promising preclinical and clinical outcomes in SZ (Harich et al, 2007, Shimazaki et al, 2010, Clifton et al, 2013Chaki et al, 2015;Hirayasu et al, 2016;Kantrowitz et al, 2016Kantrowitz et al, , 2017Kantrowitz et al, , 2019Luesson et al, 2022& Deiana et al, 2022. Aiming at restoring a normal inhibitory control in local microcircuits could also be of interest for drug developers working on SZ social dysfunction.…”

Section: Implications For Translational Research and Drug Developmentmentioning

confidence: 99%

Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia

Adraoui¹,

Douw²,

Martens³

et al. 2023

Preprint

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Schizophrenia (SZ) is a devastating psychiatric disorder affecting 1% of the world population. Social cognition impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the cellular level, an interplay between oxidative stress, inflammation and N-methyl-D-aspartate (NMDA) receptor hypofunction is thought to underly SZ pathology. At the whole-brain level, a reduced activation of social brain regions and a decrease in inter-regional connectivity within the social brain have been identified as major contributors to social cognition impairment in SZ. However, it is not clear how these pathological processes at the cellular level lead to whole-brain dysconnectivity in the origin of social cognition impairments. Aiming at bridging the gap between microscale (molecular and cellular mechanisms) and macroscale (whole-brain) knowledge, in this review, we propose impaired myelination and glial cell death in white matter tracts as possible intermediate biological pathways. Furthermore, we recommend electroencephalography as a promising translational technique that could revolutionize pre-clinical drug development research and discuss promising drug targets for the treatment of SZ social cognition impairment.

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Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents

Cited by 10 publications

References 61 publications

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

NEDD4L-Sp1 ubiquitination inhibits GlyT1 to promote prominent hippocampal neuronal damage and apoptosis, leading to cognitive dysfunction in diabetic rats

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia

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