Models of schizophrenia in humans and animals based on inhibition of NMDA receptors

Bubeníková-Valešová, Věra; Horáček, Jiří; Vrajová, Monika; Höschl, Cyril

doi:10.1016/j.neubiorev.2008.03.012

Cited by 303 publications

(217 citation statements)

References 159 publications

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“…We show that the acute impact of dizocilpine on miR-219 coincides with the expression of locomotor deficits, indicating a rapidly on-setting regulatory role of the microRNA in neurobehavioral dysfunction. Additionally, it is well known that there are compensatory physiological changes in animals chronically treated with dizocilpine, which shifts the balance of the neurotransmitter system and the corresponding neurological impairment, including significant changes in cognitive tests and the induction of locomotor activity with exposure to stress (40). The adaptive cellular changes in chronically treated mice are consistent with our finding that miR-219 is unaltered following chronic dizocilpine administration.…”

Section: Discussionsupporting

confidence: 90%

“…Acute treatment of rodents with an NMDA-R antagonist (dizocilpine) has been reported to resemble the metabolic changes in patients experiencing an acute state of psychosis (40). We show that the acute impact of dizocilpine on miR-219 coincides with the expression of locomotor deficits, indicating a rapidly on-setting regulatory role of the microRNA in neurobehavioral dysfunction.…”

Section: Discussionmentioning

confidence: 73%

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MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Kocerha

Faghihi

López‐Toledano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

272

218

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cerebral cortex ͉ glutamatergic signaling ͉ regulatory RNA N MDA receptors (NMDA-R) control many executive brain functions, such as working memory, and their dysfunction is implicated in a host of brain disorders (1-4). Notably, hypofunctional NMDA-R signaling, particularly in the prefrontal cortex (PFC), has been implicated in the cognitive and behavioral disturbances characteristic of schizophrenia (5), autism (6, 7), attention deficit hyperactivity disorder (ADHD) (8, 9), mood disorders (10), and other psychiatric illnesses. The cellular mechanisms by which disrupted NMDA-R transmission drives behavioral pathology are still unclear, although several of the major proteins involved in this pathway, such as calcium/calmodulin-dependent protein kinase II (CaMKII) (11), have been identified. In this study, we examine whether neurobehavioral abnormalities associated with NMDA-R hypofunction can be attributed to a novel class of regulatory RNA molecules, microRNAs (miRNAs).miRNAs have attracted much attention as regulators of neuronal development and synaptic plasticity (12-15). Furthermore, psychiatric disorders such as schizophrenia, autism, and Tourette's syndrome are associated with dysregulated levels of miRNAs (16)(17)(18)(19)(20). miRNAs are small (Ϸ22 nt) noncoding transcripts that can control expression of protein-coding mRNAs at the posttranscriptional level (21). Pleiotropic miRNAs can control gene expression by binding to complementary sequences in the 3Ј untranslated region (3Ј UTR) of target mRNA transcripts to facilitate their degradation and/or inhibit their translation (15,22,23). Understanding this layer of gene regulation therefore promises to enrich our knowledge of brain function and pathology. Dizocilpine is a highly selective phencyclidine-like NMDA-R antagonist that can rapidly produce schizophrenia-like behavioral deficits in humans and rodents (24). We examined whether a psychotomimetic dose of dizocilpine (0.5 mg/kg, i.p.) altered miRNA expression in brain regions of C57BL/6 mice, by using miRNA microarray profiling as an initial screening approach. Our analysis was focused on the PFC because of the considerable evidence linking this brain region with behavioral pathology in psychiatric illnesses (19). We extracted the small RNAs from the PFC of the mice 15 min after administration of a single dose of dizocilpine, i.e., a time-point at which dizocilpine-induced behavioral disturbances such as hyperlocomotion and stereotypy are readily observed (25). Of note, there was a robust reduction of miR-219 out of 182 miRNAs detectable by microarray in PFC tissues (Table S1). miR-219 is a conserved miRNA expressed in both rodent and human brains, but not in other tissues (26,27). These data demonstrate that concentrations of a brain-specific miRNA, which may play a role in regulating NMDA-R function, are altered during states of NMDA-R hypofunction.In support of the microarray data, RT-PCR analyses demonstrated that miR-219 levels were significantly reduced by Ϸ50% (a change from an average cycle th...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 73%

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Kocerha

Faghihi

López‐Toledano

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

272

218

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“…Besides PCP and MK-801, ketamine has also been used to model schizophrenia symptoms in rodents (Adler et al 1999, Bubenikova-Valesova et al 2008, Large 2007. This drug is able to induce hyperlocomotion, stereotypy, as well as deficits in attentional and memory processes in rodents (Chan et al 2008, Imre et al 2006, Neves et al 2013, Pietersen et al 2007, Pitsikas et al 2008, Rodvelt et al 2008, Wang et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Neves

Borsoi

Antonio

et al. 2017

An. Acad. Bras. Ciênc.

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Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine subanesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

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“…26,[29][30][31] The behavioural readouts are thought to correspond to the positive, negative and cognitive symptoms as seen in human schizophrenia. Fewer studies have been performed at the physiological and molecular level, although these have implicated abnormalities of neurotransmitter release and levels, 16,28,[32][33][34][35] dendritic branching, and dendritic spine number, synaptic loss, 36 along with hypofrontality.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

et al. 2015

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Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to a broad range of symptoms and wide heterogeneity, current therapeutic approaches in schizophrenia fail to treat all symptomatic manifestations of the disease. Therefore, new models that reproduce core pathological features of schizophrenia are needed for the elucidation of unidentified pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatographymass spectrometry (LC-MS) proteomic and metabonomic profiling analysis combined with targeted proteomics (selected reaction monitoring and multiplex-immunoassay) of serum and brain tissues from a chronic phencyclidine (PCP) rat model, in which NMDA-receptor hypofunction is induced through non-competitive N-methyl-D-aspartate (NMDA) antagonism. Using multiplex immunoassay, we identified serum abnormalities in cytokines (IL-5, IL-2, IL-1β) and the fibroblast-growth factor-2 levels, as peripheral biomarkers of PCP treatment. In order to find potential novel drug targets and to elucidate the pathways associated with the disease, extensive proteomic and metabonomic brain tissue profiling was employed. This revealed a more prominent effect of chronic PCP treatment on the hippocampal proteome and metabonome compared to the frontal cortex. Bioinformatic pathway analysis confirmed the abnormalities in NMDA-receptor associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA and GABAergic signalling in the hippocampus. Metabonomic profiling revealed changes in phospho-and glycolipids, which was further supported by findings of oxidative stress (superoxide dismutase) on the protein level. These molecular changes parallel findings observed in human schizophrenia. The present study could lead to increased understanding of how perturbed glutamate receptor signalling affects other relevant biological pathways in schizophrenia and therefore support drug discovery efforts for improved treatment of patients suffering from this debilitating psychiatric disorder.

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Models of schizophrenia in humans and animals based on inhibition of NMDA receptors

Cited by 303 publications

References 159 publications

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

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