Animal Model Of Schizophrenia Research Articles

Tropisetron, an Antiemetic Drug, Exerts an Anti-Epileptic Effect Through the Activation of α7nAChRs in a Rat Model of Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti-epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined. In this study, tropisetron was intraperitoneally injected into pilocarpine-induced epileptic rats for 3 weeks. Alpha-bungarotoxin (α-bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ-aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse-associated protein (F-actin, cofilin-1) were quantified. The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m6A modification of cofilin-1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α-bgt. In summary, these findings indicate that tropisetron exhibits an anti-epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti-epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE.

Effects of Antipsychotics on the Hypothalamus-Pituitary-Adrenal Axis in a Phencyclidine Animal Model of Schizophrenia.

Schizophrenia (SCH) is a mental disorder that requires long-term antipsychotic treatment. SCH patients are thought to have an increased sensitivity to stress. The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, observed in SCH, could include altered levels of glucocorticoids, glucocorticoid receptors (GRs), and associated proteins. The perinatal administration of phencyclidine (PCP) to rodents represents an animal model of SCH. This study investigated the effects of perinatal PCP exposure and subsequent haloperidol/clozapine treatment on corticosterone levels measured by ELISA and the expression of GR-related proteins (GR, pGR, HSP70, HSP90, FKBP51, and 11β-Hydroxysteroid dehydrogenase-11β-HSD) determined by Western blot, in different brain regions of adult rats. Six groups of male rats were treated on the 2nd, 6th, 9th, and 12th postnatal days (PN), with either PCP or saline. Subsequently, one saline and one PCP group received haloperidol/clozapine from PN day 35 to PN day 100. The results showed altered GR sensitivity in the rat brain after PCP exposure, which decreased after haloperidol/clozapine treatment. These findings highlight disturbances in the HPA axis in a PCP-induced model of SCH and the potential protective effects of antipsychotics. To the best of our knowledge, this is the first study to investigate the effects of antipsychotic drugs on the HPA axis in a PCP animal model of SCH.

MGluR5 positive allosteric modulation prevents MK-801 induced increases in extracellular glutamate in the rat medial prefrontal cortex

Potentiation of metabotropic glutamate receptor subtype 5 (mGluR5) function produces antipsychotic-like and pro-cognitive effects in animal models of schizophrenia and can reverse cognitive deficits induced by N-methyl-D-aspartate type glutamate receptor (NMDAR) antagonists. However, it is currently unknown if mGluR5 positive allosteric modulators (PAMs) can modulate NMDAR antagonist-induced alterations in extracellular glutamate levels in regions underlying these cognitive and behavioral effects, such as the medial prefrontal cortex (mPFC). We therefore assessed the ability of the mGluR5 PAM, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB), to reduce elevated extracellular glutamate levels induced by the NMDAR antagonist, dizocilpine (MK-801), in the mPFC. Male Sprague-Dawley rats were implanted with a guide cannula aimed at the mPFC and treated for ten consecutive days with MK-801 and CDPPB or their corresponding vehicles. CDPPB or vehicle was administered thirty minutes before MK-801 or vehicle each day. On the final day of treatment, in vivo microdialysis was performed, and samples were collected every thirty minutes to analyze extracellular glutamate levels. Compared to animals receiving only vehicle, administration of MK-801 alone significantly increased extracellular levels of glutamate in the mPFC. This effect was not observed in animals administered CDPPB before MK-801, nor in those administered CDPPB alone, indicating that CDPPB decreased extracellular glutamate release stimulated by MK-801. Results indicate that CDPPB attenuates MK-801 induced elevations in extracellular glutamate in the mPFC. This effect of CDPPB may underlie neurochemical adaptations associated with the pro-cognitive effects of mGluR5 PAMs in rodent models of schizophrenia.

Mediated learning: A computational rendering of ketamine-induced symptoms.

This article explores the contribution of the double error dynamic asymptote computational associative learning model to understanding the role of mediated learning mechanisms in the generation of spurious associations, as those postulated to characterize schizophrenia. Three sets of simulations for mediated conditioning, mediated extinction, and a mediated enhancement of latent inhibition, a unique model prediction, are presented. For each set of simulations, a parameter that modulates the impact of associative memory retrieval and the dissipation of nonperceptual activated representations through the network was manipulated. The effect of this operation is analyzed and compared to ketamine-induced effects on associative memories and mediated learning. The model's potential to predict these effects and present a plausible error-correction associative mechanism is discussed in the context of animal models of schizophrenia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.

Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. Pregnant Sprague-Dawley rats were treated with MAM (22mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography–mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Maternal immune activation induces sex-dependent behavioral differences in a rat model of schizophrenia.

Maternal immune activation (MIA) is a mature means to construct a schizophrenia model. However, some preclinical studies have reported that a MIA-induced schizophrenia model seemed to have gender heterogeneity in behavioral phenotype. On the other hand, the MIA's paradigms were diverse in different studies, and many details could affect the effect of MIA. To some extent, it is not credible and scientific to directly compare the gender differences of different MIA programs. Therefore, it is necessary to study whether the sex of the exposed offspring leads to behavioral differences on the premise of maintaining a consistent MIA mode. An animal model of schizophrenia was established by the administration of 10 mg/kg Poly (I: C) when dams were on day 9 of gestation. Then, a number of female and male offspring completed a series of behavioral tests during postnatal days 61-75. Compared with the female control group (n = 14), female MIA offspring (n = 12) showed a longer movement distance (d = 1.07, p < 0.05) and higher average speed (d = 1.08, p < 0.05) in the open field test (OFT). In the Y maze test, the percentage of entering the novel arm of female MIA offspring was lower (d = 0.92, p < 0.05). Compared with the male control group (n = 14), male MIA offspring (n = 13) displayed less movement distance (d = 0.93, p < 0.05) and a lower average speed (d = 0.94, p < 0.05) in the OFT. In the Y maze test, the proportion of exploration time in the novel arm of male MIA offspring was lower (d = 0.96, p < 0.05). In the EPM, male MIA offspring showed less time (d = 0.85, p < 0.05) and a lower percentage of time spent in the open arms (d = 0.85, p < 0.05). Male MIA offspring also had a lower PPI index (76 dB + 120 dB, d = 0.81, p < 0.05; 80 dB + 120 dB, d = 1.45, p < 0.01). Our results showed that the behavioral phenotypes induced by prenatal immune activation were highly dependent on the sex of the offspring.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice

BackgroundMuscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. MethodsNovel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. ResultsF15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. ConclusionOur results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

Oxidative Stress in Schizophrenia: Relation to Neurochemical Pathogenetic Hypotheses

Background: heterogeneity of schizophrenia is reflected in the variety of clinical manifestations and biological disorders, on the basis of which several neurochemical hypotheses are formulated for schizophrenia pathogenesis. Review of the current hypotheses of schizophrenia pathogenesis shows that oxidative stress is not the main cause of the disease development, but affects its course and contributes to the deterioration of the patient’s condition. Objective: analysis of the relationships between redox imbalance and oxidative stress and the development of pathological processes in schizophrenia within the framework of neurochemical hypotheses of the disease pathogenesis. Material and methods: a search was made for sources in the Medline/PubMed databases, Scopus and RSCI using keyword combinations “oxidative stress”, “oxidation-reduction imbalance”, “schizophrenia”, “hypotheses of schizophrenia pathogenesis”, “antioxidants”, “neurotransmitters”, “glutathione”, “neuroinflammation”. Conclusion: data from numerous studies of the brain of patients with schizophrenia, their blood plasma, serum, and blood cells as well as the study of animal models of schizophrenia indicate the presence of redox imbalance and oxidative stress in this disease. Taken together, these data indicate that genetic and environmental factors that affect the manifestation of various pathological mechanisms in schizophrenia (disturbances in neurotransmitter systems, hypofunction of N-methyl-D-aspartate receptors, neuroinflammation, impaired signaling protein phosphorylation pathways) lead to the oxidative stress, enhancing the initial pathological changes, as a result of which synchronization processes and intercellular communications in the brain become disrupted. Medicines with antioxidant and anti-inflammatory properties, compounds for correcting mitochondrial dysfunction, and NMDAR-mediated signaling modulators can be used as drugs to reduce the harmful effects of oxidative stress. The efficacy of these medicines may vary in different patients, so the development of biomarker systems aimed at identifying individuals who are more likely to respond to a particular drug is of great importance.

Network analysis on Homer1a-expression in schizophrenia animal model and synaptic modulation by dopamine D2R antagonist

Network analysis on Homer1a-expression in schizophrenia animal model and synaptic modulation by dopamine D2R antagonist

Unraveling the role of Slc10a4 in auditory processing and sensory motor gating: Implications for neuropsychiatric disorders?

BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of the Slc10a4 gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4−/−), leads to the accumulation of extracellular dopamine. A major challenge for studying schizophrenia is the lack of suitable animal models that accurately represent the disorder. We sought to overcome this challenge by using Slc10a4−/− mice as a potential model, considering their altered dopamine levels. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain. MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) of Slc10a4−/− mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT and Slc10a4−/− mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior. ResultsBaseline locomotion during auditory stimulation was similar between Slc10a4−/− mice and WT littermates. In WT animals, normal auditory processing was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand, Slc10a4−/− mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment in Slc10a4−/− mice, which was not observed in WT littermates. Prepulse inhibition was also decreased in Slc10a4−/− mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates. ConclusionThe Slc10a4−/− mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest that Slc10a4−/− mice can be considered as potential models for neuropsychiatric conditions.

The role of SIRT3 in mediating the cognitive deficits and neuroinflammatory changes associated with a developmental animal model of schizophrenia

The neuroinflammatory state may contribute to the pathogenesis of many mental disorders including schizophrenia. Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for activation of proteins involved in mitochondria quality control, such as Sirtuin3 (SIRT3). Our previous study has found that NAD+ supplement could rescue early life stress (ELS)-induced neuroinflammation and down-regulation of SIRT3 in adult offspring. However, it is unclear whether SIRT3 is the key to the neuroprotective effects of NAD+ supplement in this animal model of schizophrenia. The present study used 24 h maternal separation (MS) as ELS to Wistar rat pups on the postnatal day (PND) 9. Schizophrenia-like behaviors and memory impairments were detected by behavioral tests. Microglial activation, pro-inflammatory cytokine expression, and NAD+/SIRT3 expression were detected in the prefrontal cortex and hippocampus. Meanwhile, NAM (a precursor of NAD+), and the SIRT3 activator Honokiol (HNK), and the SIRT3 inhibitor 3-TYP were used as an intervention in vivo. Our results showed that ELS could induce schizophrenia-like behaviors and M1 microglial activation, NAD+ decline, lower expression of SIRT3, and increased acetylated superoxide dismutase 2 expression at the adult stage. NAD+ supplement or HNK administration could block this process and normalize the behavioral alterations of the MS animals. 3-TYP administration in the control group and the NAM-treated MS rats caused M1 microglial activation and cognitive deficits. Our results demonstrated that SIRT3 mediated the stabilizing effect of NAD+ on normalizing M1 microglial activation and behavioral phenotypes in MS rats.

Behavioral and transcriptional effects of repeated electroconvulsive seizures in the neonatal MK-801-treated rat model of schizophrenia.

Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear. To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia. Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted. Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E. E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT.

Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia

One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2–3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.

Role of MAPK and PI3K-Akt signaling pathways in cuprizone-induced demyelination and cognitive impairment in mice

This study aimed to find the genes and signaling pathways underlying cuprizone-induced demyelination and cognitive impairments in mice. We used the cuprizone-exposed mice as an animal model of schizophrenia and assessed cognitive function in mice. Total RNA was extracted from mouse brain tissues for RNA sequencing. The DESeq2 R package was utilized to analyze the differentially expressed genes (DEGs). Functional and pathway enrichment analyses were performed simultaneously. We also constructed a protein-protein interaction (PPI) network to screen potential hub genes, and quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the screened genes. After 6 weeks of cuprizone treatment, the cognitive function of mice was impaired. Compared to the controls, the cuprizone-exposed mice contained 351 DEGs, including 167 upregulated and 184 downregulated genes. Enrichment analysis showed that the DEGs were enriched in some biological processes involved in demyelination, including the MAPK pathway. Functional pathway analysis revealed that the DEGs were significantly enriched in the PI3K-Akt signaling pathway, which may be associated with cognitive impairments. MBP, IGF1, GFAP, PTPRC, CD14, CD68, ITGB2, LYN, TLR2, TLR4, VAV1, and PLEK were considered as potential hub genes. Except for MBP, all genes were upregulated in the cuprizone models, as verified by qRT-PCR. We suggest that the MAPK and PI3K-Akt signaling pathways may be associated with demyelination and cognitive impairments, respectively. GFAP and IGF-1 expression levels increased in cuprizone-exposed mice, suggesting that astrocytes may play a role in protecting the myelin sheath following treatment with cuprizone.

A new approach to explore the correlation between declarative memory and anxiety in animal models of schizophrenia and microplastic pollution

The discovery of new detrimental effects associated with microplastic pollution is ever-growing and reaching alarming rates worldwide, as it is linked to numerous disorders such as lung diseases, gastrointestinal problems, and cancer. However, a less explored issue is their impact on mental health, more precisely schizophrenia, even though several studies have shown the presence of microplastics in air, water, soil, and even food, thus making them a significant part of our daily dietary intake. It is also well known that declarative memory and anxiety levels are impaired in schizophrenia. However, apart from the novel object recognition test, the possibilities for testing memory in zebrafish are quite limited. For these reasons, we designed a novel memory test based on rewards, a learning period, and zebrafish's natural preference for certain colors. Among the results, our fish preferred the color yellow over red, and we illustrated that ketamine and its combination with methionine provide a robust model that seems to better represent the aspects of schizophrenia in animal models. Moreover, surprisingly, we observed that microplastics (more precisely, polypropylene fibers) ingested by animals through the diet seem to act as a buffer against ketamine toxicity and as an enhancer for methionine exposure. Moreover, according to our results, groups with higher anxiety levels seem to perform better on the memory test.

Effects of Nicotine Administration in an Enriched Environment on the Behavior of Male MK-801-Exposed Rats.

Smoking is more common in patients with schizophrenia than in healthy populations. Some controversial hypotheses connect the disease with the high prevalence of smoking. Moreover, environmental factors affect the severity of the positive and negative symptoms of schizophrenia. The current study aimed to assess the effect of enriched environment (EE) and nicotine on the MK-801 animal model of schizophrenia. Male Wistar rat pups randomly received saline or MK-801 (dose:1 mg/kg) for five days from the sixth postnatal day (P) until the tenth. The pups were placed in EE or standard cages (SCs) after weaning (P21). Morris water maze (MWM) was used to assess spatial learning and memory. The rats received 0.6 mg/kg nicotine twice for three days at the end of the second month and were examined in an open-field box and three-chamber social interaction test. MK-801 rats' behaviors were the same as those of the saline rats when they were exposed to nicotine. No positive effects of EE were observed when the animals were exposed to nicotine. The results suggested that nicotine decreased schizophrenia-like symptoms and covered the positive effects of EE.

Fundamental disincorporation and early non-inflammatory microglia alterations: Possible bridging phenomena between neurobiology and psychopathology in schizophrenia

Increasing evidence shown that schizophrenia (SCZ) is associated with immunological aberrations. Particularly, microglia, the resident innate immune cells of the brain, have been implicated in SCZ pathogenesis. However, despite the abundance of empirical findings highlighting the role of microglia-mediated neuroinflammation in the neuropathology development in a wide range of central nervous system (CNS) disorders, non-inflammatory abnormalities in this cellular compartment have been associated with neuropsychiatric manifestation of SCZ in some postmortem works and in SCZ animal models. We hypothesize that at least some of these non-inflammatory perturbations represent the core neurobiological features of a “disincorporated” state of microglia in SCZ and indicate a switch from homeostatic coupling/functional response to maladaptive reaction to environmental inputs. This work aims to summarize experimental evidence that support this possible novel conceptual paradigm. This hypothesis needs further confirmations. In summary, the possible role of microglia in the pathogenesis of SCZ is certainly complex with conflicting evidence. Therefore, new conceptual paradigms useful for capturing the fundamental alterations of microglia seem to be required. Considering the need for experimental confirmation, the ecological idea of microglial disincorporation might be a first step in this direction, sufficiently supported by recent literature.