Neuropharmacology
Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. Electronic address:
Published: August 2022
Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.
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http://dx.doi.org/10.1016/j.neuropharm.2022.109079 | DOI Listing |
Schizophr Bull
August 2024
Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
Background And Hypothesis: N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity.
Study Design: This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis.
Nihon Yakurigaku Zasshi
May 2023
Department of Organ Anatomy, Tohoku University Graduate School of Medicine.
Our previous study has suggested that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathophysiology of schizophrenia. In the current study, we screened and identified rare variants in the PPARA gene (encoding PPARα) of schizophrenia subjects. In vitro study showed that those variants decreased activities of PPARα as a transcription factor.
View Article and Find Full Text PDFEur J Pharmacol
November 2022
Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. of CNS Discovery Research, Biberach an der Riss, Germany.
N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR signalling can be enhanced by increasing extracellular levels of the NMDAR co-agonist glycine through inhibition of its transporter (GlyT1). This may be one option to improve cognitive deficits or negative symptoms of schizophrenia.
View Article and Find Full Text PDFInt J Mol Sci
May 2022
Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland.
Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia.
View Article and Find Full Text PDFNeuropharmacology
August 2022
Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Vic, Spain. Electronic address:
Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
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