Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits

Hamieh, Al Mahdy; Babin, David; Sablé, Evelyne; Hernier, Anne Marie; Castagné, Vincent

doi:10.1007/s00213-020-05700-y

Cited by 9 publications

(20 citation statements)

References 50 publications

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“…Perinatal NMDA receptor antagonists combined with postweaning social isolation induce abnormal behavior, anxiety-like symptoms, and cognitive impairment more consistent with the symptoms of SCZ, which have also been reported in many animal models [10,22,[40][41][42]. Therefore, based on previous studies, we constructed an animal model of SCZ neurodevelopment, in which SCZ-like sensory gating disorders, positive symptoms, negative symptoms, anxity-like behaviors, and learning and memory impairment were successfully replicated.…”

Section: Discussionmentioning

confidence: 75%

“…A large amount of evidence, such as gene variation and defects, infection during pregnancy, and perinatal hypoxia, suggests that SCZ is a neurodevelopmental disorder [6][7][8][9]. Studies have shown that repeated NMDA receptor antagonist injections during neurodevelopment are more effective at replicating SCZrelated abnormal behaviors, such as in the neonatal NMDA receptor antagonist model MK-801 treatment on postnatal day 5 (P5) or P7 [10][11][12]. On the other hand, adolescence may be a sensitive period of vulnerability to environmental damage, which is seen as a second blow to induce disease [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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FTO ameliorates learning and memory impairment by activating PI3K/AKT/mTOR signaling pathway in a neurodevelopmental model of schizophrenia

li,

Zhong,

Zhang

et al. 2024

Preprint

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Background The pathogenesis of cognitive dysfunction in schizophrenia (SCZ) is still unclear, and m6A methylation may be involved in the neuropsychiatric diseases. The aim of this study was to investigate the effect of m6A methylation on learning and memory impairment induced by a neurodevelopmental model of SCZ. Methods Perinatal NMDA receptor antagonist combined with post-weaning social isolation (MK-SI) was used to construct a neural development model of SCZ. FTO adeno-associated virus (AAV) was injected into the hippocampus by stereotaxic technique. Then, it is evaluated by a series of behavioral tests. Brain tissue was analyzed by m6A dot blot, LC-MS/MS, qRT-PCR, western blot, tissue staining, MeRIP-seq, and colorimetry. Results Our results showed that FTO mediates m6A modification in the hippocampus of MK-SI mice, leading to learning and memory impairment. AAV9 FTO knockdown (FTO-KD) aggravated learning and memory impairment induced by MK-SI model. In contrast, AAV9 FTO overexpression (FTO-OE) reversed these effects. In addition, FB23-2 inhibited the reversal effect of FTO-OE in MK-SI mice, further confirming the important role of FTO in MK-SI-induced learning and memory impairment. Next, using high-throughput sequencing analysis, we found that the PI3K/AKT/mTOR signaling pathway may play a key role. In addition, the expression of the apoptotic protein Bax and the pro-apoptotic protein Bcl-2 were regulated by FTO. Conclusions In summary, the demethylase FTO mediated m6A modification to induce learning and memory impairment, highlighting the important role played by FTO in cognitive dysfunction in the MK-SI model.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

FTO ameliorates learning and memory impairment by activating PI3K/AKT/mTOR signaling pathway in a neurodevelopmental model of schizophrenia

li,

Zhong,

Zhang

et al. 2024

Preprint

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“…Through different study selection processes, 17 articles met the inclusion criteria for this systematic review [ 33 , 34 , 35 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Eight studies used Sprague Dawley rats [ 34 , 39 , 40 , 41 , 42 , 43 , 44 , 48 ], three studies used Lister-hooded rats [ 46 , 47 , 49 ], three studies used Wistar rats [ 38 , 45 , 50 ], and another three studies used mice [ 33 , 35 , 51 ]. All studies used male animals except one that used both male and female animals [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…All studies used male animals except one that used both male and female animals [ 45 ]. Most studies originated from Europe; the United Kingdom [ 46 , 47 , 49 ], and Spain [ 33 , 35 , 51 ] each had three studies, Hungary [ 38 , 45 ] had two, while France [ 50 ] and Germany [ 44 ] had one each. North America (Canada) produced five papers [ 39 , 40 , 41 , 42 , 43 ], and Asia (China) two papers [ 34 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

“…Ten studies found that the “double hit” model is more effective when compared to the intervention using social isolation on its own or an NMDA receptor antagonist [ 33 , 35 , 40 , 44 , 45 , 46 , 47 , 49 , 50 , 51 ]. Three of these studies were able to produce positive symptoms of schizophrenia, which is the impairment on the locomotor activity [ 40 , 47 , 50 ].…”

Section: Resultsmentioning

confidence: 99%

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Investigating the Robustness of a Rodent “Double Hit” (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review

2023

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Schizophrenia is a debilitating psychiatric disorder comprising positive, negative, and cognitive impairments. Most of the animal models developed to understand the neurobiology and mechanism of schizophrenia do not produce all the symptoms of the disease. Therefore, researchers need to develop new animal models with greater translational reliability, and the ability to produce most if not all symptoms of schizophrenia. This review aimed to evaluate the effectiveness of the rodent “double hit” (post-weaning social isolation and N-methyl-D-aspartate (NMDA) receptor antagonist) model to produce symptoms of schizophrenia. This systematic review was developed according to the 2020 PRISMA guidelines and checklist. The MEDLINE (PubMed) and Ebscohost databases were used to search for studies. The systematic review is based on quantitative animal studies. Studies in languages other than English that could be translated sufficiently using Google translate were also included. Data extraction was performed individually by two independent reviewers and discrepancies between them were resolved by a third reviewer. SYRCLE’s risk-of-bias tool was used to test the quality and biases of included studies. Our primary search yielded a total of 47 articles, through different study selection processes. Seventeen articles met the inclusion criteria for this systematic review. Ten of the seventeen studies found that the “double hit” model was more effective in developing various symptoms of schizophrenia. Most studies showed that the “double hit” model is robust and capable of inducing cognitive impairments and positive symptoms of schizophrenia.

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SEP‐363856 exerts neuroprotection through the PI3K/AKT/GSK‐3β signaling pathway in a dual‐hit neurodevelopmental model of schizophrenia‐like mice

Li,

Liu,

Sun

et al. 2024

Drug Development Research

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Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it's important to pay attention to the adverse effects as well. Clinical studies for SZ are currently in phase ΙΙΙ for SEP‐363856 (SEP‐856)‐a new antipsychotic that doesn't work on dopamine D2 receptors. However, the underlying action mechanism of SEP‐856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP‐856 on SZ‐like behavior in a perinatal MK‐801 treatment combined with social isolation from the weaning to adulthood model (MK‐SI). First, we created an animal model that resembles SZ that combines the perinatal MK‐801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP‐856. The levels of proinflammatory cytokines (tumor necrosis factor‐α, interleukin‐6, and interleukin‐1β), apoptosis‐related genes (Bax and Bcl‐2), and synaptic plasticity‐related genes (brain‐derived neurotrophic factor [BDNF] and PSD‐95) in the hippocampus were analyzed by quantitative real‐time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD‐95, Bax, Bcl‐2, PI3K, p‐PI3K, AKT, p‐AKT, GSK‐3β, p‐GSK‐3β in the hippocampus. MK‐SI neurodevelopmental disease model studies have shown that compared with sham group, MK‐SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK‐SI model can mimic symptoms similar to those of SZ. Compared with the MK‐SI model, high doses of SEP‐856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK‐SI mice. In addition, SEP‐856 can reduce the release of proinflammatory factors in the MK‐SI model, promote the expression of BDNF and PSD‐95 in the hippocampus, correct the Bax/Bcl‐2 imbalance, turn on the PI3K/AKT/GSK‐3β signaling pathway, and ultimately help the MK‐SI mice's behavioral abnormalities. SEP‐856 may play an antipsychotic role in MK‐SI “dual‐hit” model‐induced SZ‐like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro‐inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK‐3β signaling cascade.

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Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits

Cited by 9 publications

References 50 publications

FTO ameliorates learning and memory impairment by activating PI3K/AKT/mTOR signaling pathway in a neurodevelopmental model of schizophrenia

FTO ameliorates learning and memory impairment by activating PI3K/AKT/mTOR signaling pathway in a neurodevelopmental model of schizophrenia

Investigating the Robustness of a Rodent “Double Hit” (Post-Weaning Social Isolation and NMDA Receptor Antagonist) Model as an Animal Model for Schizophrenia: A Systematic Review

SEP‐363856 exerts neuroprotection through the PI3K/AKT/GSK‐3β signaling pathway in a dual‐hit neurodevelopmental model of schizophrenia‐like mice

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