Schizophrenia-like Model Research Articles

Dopamine D1 receptors activation rescues hippocampal synaptic plasticity and cognitive impairments in the MK-801 neonatal schizophrenia model

Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7–11 postnatal days, PND). We evaluated synaptic plasticity late-LTP and spatial memory consolidation in early adolescence and young adulthood using extracellular field recordings in acute hippocampal slices and the Barnes maze task. Next, we examined D1 receptor (D1R) activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of dopamine D1R ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia.

Vortioxetine improved schizophrenia-like behavioral deficits in a Poly I:C-induced maternal immune activation model of schizophrenia in rats.

Several studies provide clear evidence that exposure to various infections during pregnancy are linked with an increased risk for schizophrenia. In preclinical studies, administration of polyinosinic-polycytidylic acid (Poly I:C) in pregnant rodents can induce maternal immune activation leading to impairments in brain function in the offspring. The aim of this study was to investigate the effect of vortioxetine, a multimodal selective serotonin reuptake inhibitor (SSRI), in the pathophysiology of Poly I:C-induced schizophrenia-like model in rats. For this purpose, Poly I:C (8 mg/kg, ip) was injected into pregnant animals 14 days after mating, and tail blood was taken for determination of IL-6 levels after 2 h. At postnatal days 83-86, behavioral tests were performed. Our results revealed that Poly I:C caused impairments in prepulse inhibition, novel object recognition, social interaction, and open-field tests. Chronic administration of vortioxetine (2.5, 5, and 10 mg/kg, ip, postnatal days 69-83) caused significant improvements in these deficits. Overall, our findings indicate that vortioxetine may provide new therapeutic approaches for the treatment of schizophrenia. We think that increased serotonergic activity in frontal brain regions may provide the ameliorative effect of vortioxetine, especially on negative and cognitive symptoms. Therefore, it will be useful to determine the efficacy of vortioxetine with combined drugs with further studies.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 μM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 μM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Effects of Nostoc commune extract on the cerebral oxidative and neuroinflammatory status in a mice model of schizophrenia

Cyanobacterium Nostoc commune has long been used to alleviate various diseases. This research examines the effects of Nostoc commune extract (NCE) against behavioral disorders, cerebral oxidative stress, and inflammatory damage in the ketamine-induced schizophrenia model. Oral NCE administration (70 and 150 mg/kg/d) is performed after intraperitoneal ketamine injection (20 mg/kg) for 14 consecutive days. The forced swimming and open field tests are used to assess schizophrenia-like behaviors. After the behavioral test, dopamine (DA) level, oxidative stress markers, as well as the interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression are measured in the cerebral cortex. The results show that NCE treatment ameliorates KET-induced anxiety and depressive-like behaviors in OFT and FST, respectively. NCE considerably decreases the malondialdehyde (MDA) and DA levels and IL-6 and TNF-α expressions in mice with schizophrenia-like symptoms. Also, a significant increase is observed in the glutathione (GSH) level and catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GRx) activity in cerebral tissue. The present study shows that NCE treatment effectively improves KET-induced schizophrenia-like behaviors and oxidative and inflammatory damage. Therefore, NCE, via its bioactive constituents, could have strong neuroprotective effects in the schizophrenia-like model.

Putative neural mechanisms underlying release-mode-specific abnormalities in dopamine neural activity in a schizophrenia-like model: The distinct roles of glutamate and serotonin in the impaired regulation of dopamine neurons.

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N-methyl-d-aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs.

Innate immune system alterations in frontal cortex and hippocampus of a “double-hit” schizophrenia like-model

Innate immune system alterations in frontal cortex and hippocampus of a “double-hit” schizophrenia like-model

Interacting effects of the MAM model of schizophrenia and antipsychotic treatment: Untargeted proteomics approach in adipose tissue

Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.

Involvement of nicotinic acetylcholine receptors in behavioral abnormalities and psychological dependence in schizophrenia-like model mice

The smoking incentive in patients with schizophrenia (SCZ) depends on stimulation of nicotinic acetylcholine receptors (nAChRs) in the central nervous system. To detect potential predictor genes for nicotine responses in SCZ, we explored common factor using research data in human and animal samples. In lymphoblastoid cell lines from SCZ, the mRNA expression level of α7 nAChR subunit was decreased. In SCZ-like model mice of phencyclidine (PCP; 10 mg/kg/day, subcutaneously for 14 days)-administered mice, the mRNA expression level of α7 nAChR subunit and protein expression level of α7 or α4 nAChR subunit were significantly decreased in the prefrontal cortex during PCP withdrawal. Protein, but not mRNA, expression levels of α7, α4, and β2 nAChR subunits were significantly increased in the nucleus accumbens. Acute (-)-nicotine [(-)-NIC: 0.3 mg/kg, s.c.] treatment attenuated impairments of social behaviors and visual recognition memory. These effects of (-)-NIC were completely blocked by both methyllycaconitine, a selective α7 nAChR antagonist, and dihydro-β-erythroidine (DHβE), a selective α4β2 nAChR antagonist. (-)-NIC did not induce conditioned place preference, but enhanced sensitivity to methamphetamine-induced hyperactivity. These findings suggest that α7 nAChR is associated with development of disease and is implicated in the therapeutic effect of nicotine in SCZ. The smoking incentive in SCZ might be attributed to treat their own symptoms, rather than a result of (-)-NIC dependence, by stimulating α7 and/or α4β2 nAChRs.

Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long-acting formulation

Mortality in psychiatric patients with severe mental illnesses reaches a 2–3 times higher mortality rate compared to the general population, primarily due to somatic comorbidities. A high prevalence of cardiovascular morbidity can be attributed to the adverse metabolic effects of atypical antipsychotics (atypical APs), but also to metabolic dysregulation present in drug-naïve patients. The metabolic aspects of neurodevelopmental schizophrenia-like models are understudied. This study evaluated the metabolic phenotype of a methylazoxymethanol (MAM) schizophrenia-like model together with the metabolic effects of three APs [olanzapine (OLA), risperidone (RIS) and haloperidol (HAL)] administered via long-acting formulations for 8 weeks in female rats. Body weight, feed efficiency, serum lipid profile, gastrointestinal and adipose tissue-derived hormones (leptin, ghrelin, glucagon and glucagon-like peptide 1) were determined. The lipid profile was assessed in APs-naïve MAM and control cohorts of both sexes.Body weight was not altered by the MAM model, though cumulative food intake and feed efficiency was lowered in the MAM compared to CTR animals. The effect of the APs was also present; body weight gain was increased by OLA and RIS, while OLA induced lower weight gain in the MAM rats. Further, the MAM model showed lower abdominal adiposity, while OLA increased it. Serum lipid profile revealed MAM model-induced alterations in both sexes; total, HDL and LDL cholesterol levels were increased. The MAM model did not exert significant alterations in hormonal parameters except for elevation in leptin level. The results support intrinsic metabolic dysregulation in the MAM model in both sexes, but the MAM model did not manifest higher sensitivity to metabolic effects induced by antipsychotic treatment.

Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats.

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.

P.110 Inflammasomes in “double hit” schizophrenia like-models: new perspectives in the study of psychosis

There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were daily injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline during pregnancy, and we tested prepulse inhibition –PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R+ granulocytes in the LPS-offspring and an exciting trend for CB2R+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R+ granulocytes and possibly CB2R+ lymphocytes could be potential biomarkers of schizophrenia.

The impact of D-cycloserine and sarcosine on in vivo frontal neural activity in a schizophrenia-like model

BackgroundN-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo.MethodsBy using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice.ResultsIn vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice.ConclusionsWe conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

Nardostachys jatamansi Targets BDNF-TrkB to Alleviate Ketamine-Induced Schizophrenia-Like Symptoms in Rats

Schizophrenia, a common neurological disorder appearing in the late teens or early adulthood, is characterized by disorganized thinking, behaviour, and perception of emotions. Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated synaptic plasticity is a major pathological event here due to dysfunction of dopamine and glutamate transmission at NMDA receptors. De-regulated brain-derived neurotrophic factor (BDNF), i.e., its signalling through the tropomyosin receptor kinase B (TrkB) receptor, is a major feature of schizophrenia. With recent global awareness of traditional plant medicines in reducing side effects, the aim of our study was to evaluate the efficacy of the ethanolic root extract of a herb belonging to the Valerianacea family, Nardostachys jatamansi, against ketamine-induced schizophrenia-like model in rats. The effect of the N. jatamansi drug (oral dosage of 500 mg/kg body weight for 14 days) in ketamine-administered male Wistar albino rats (30 mg/kg body weight for 5 days) on modulating behaviour and the level of neurotransmitters like dopamine and glutamate was studied in whole-brain homogenates, and its influence on BDNF and TrkB levels in 2 relevant brain regions, the hippocampus and prefrontal cortex, was assessed. We observed that N. jatamansi treatment exhibited encouraging results in the modulation of ketamine-induced schizophrenia-like behaviours, principally the positive symptoms. Our drug both significantly upregulated the glutamate level and downregulated the dopamine level in whole-brain homogenates and retained the normal levels of BDNF (in the hippocampus but not in the prefrontal cortex) and TrkB (in both hippocampus and prefrontal cortex) induced by ketamine in rats. These findings suggest a neuroprotective effect of the ethanolic root extract of N. jatamansi against ketamine-induced schizophrenia-like symptoms in rats; possibly, regarding its effect on TrkB signalling. Further research is warranted in the treatment of schizophrenic symptoms.

Effects of SPAK knockout on sensorimotor gating, novelty exploration, and brain area-dependent expressions of NKCC1 and KCC2 in a mouse model of schizophrenia.

SPAK (Sterile 20/SPS1-related proline/alanine-rich kinase) is a protein kinase belonging to the mitogen-activated protein kinase (MAPK) superfamily that has been found to be extensively distributed across the body. The SPAK downstream substrates NKCC1 and KCC2 in the central nervous system are important in the interpretation of developmental mental disorders. The present study aimed to clarify the role of SPAK-NKCC1/KCC2 using a rodent schizophrenia-like model. The mouse paradigm of isolation rearing (IR) was employed, as it simulates the sensorimotor gating abnormalities of schizophrenia. SPAK transgenic mice were used and were divided into four groups: social-wild type, social-SPAK(-/-), isolation-wild type, and isolation-SPAK(-/-). The prepulse inhibition (PPI) test and the novel object recognition test (NORT) were used to measure schizophrenia-associated dysfunctions in gating ability and the novelty recognition, respectively. Finally, the protein expressions of NKCC1/KCC2 in the prefrontal cortex and hippocampus were detected to determine correlations with the behavioral data. Our results demonstrated that SPAK-null mice had superior PPI and novelty recognition relative to wild type controls, with a concomitant increase in KCC2 in the prefrontal cortex. IR disrupted PPI and NORT performances with an associated increase in KCC2. Furthermore, rearing environment and gene manipulation had mutually interactive effects, as the IR-induced effects on PPI and NORT were reversed by SPAK knockout, and the increase in KCC2 and the decreased in the NKCC1/KCC2 ratio in the prefrontal cortex induced by SPAK knockout were reversed by IR. Our data supported the gene-environment hypothesis and demonstrated the potential value of SPAK manipulation in future schizophrenia studies.

Individual gain/loss attitude, conditional cooperation, and random shifting in a public goods game

The public goods game (PGG) is an economic game that is frequently used to measure human cooperation and free-riding behavior. Various empirical studies over two decades have addressed the emergence of cooperation and the gradual propagation of free-riding. However, most of the models in the previous studies did not investigate the interactions between and dynamics of cognitive motivations. The aim of the current study was to investigate the dynamic interaction between the opposing cognitive motivations underlying free-riding and cooperation during repeated trials. We used a computational model that simulates iterative threshold PGG with binary decision-making under three different conditions. Our model consisted of a cognitive process component that encodes multiple forms of objective information, an affective process component that encodes internal states (fear, greed, and social well-being), and a random shifting component. The individual loss and gain attitudes of the agent determined the initial and converged free-riding ratios. We observed that conditional cooperation established distinguishable free-riding patterns between conditions and that the random shifting component mimicked the frequent shifting of human behavior. Furthermore, this model could be extended to a schizophrenia-like model by adjusting the integration of loss information and social well-being learning rates.

Clozapine but not haloperidol suppresses the changes in the levels of neuropeptides in MK-801-treated rat brain regions

Noncompetitive NMDA receptor antagonist (+)MK-801 is known to induce neurotoxicity and schizophrenia-like symptomatology where atypical neuroleptic clozapine is effective in contrast to typical neuroleptic, haloperidol. Although neuropeptides are implicated in memory and cognition, their roles in schizophrenia are not well understood. In the present study, we therefore examined the possible roles of neuropeptides, cholecystokinin (CCK) and somatostatin (SS) in the posterior cingulate/retrosplenial cortices (PC/RSC), frontal cortex, and hippocampus of a MK-801-induced schizophrenia-like model rat brain. This study further investigated the pretreated effect of atypical versus typical neuroleptics on the peptidergic system. SS mRNA and peptide levels significantly decreased in the PC/RSC and hippocampus but not in the frontal cortex 3 days after 0.5 mg/kg MK-801 treatment whereas CCK mRNA and peptide levels significantly decreased in all of the brain regions examined. Pretreatment with clozapine but not haloperidol completely recovered the changes in both mRNA and peptide levels of SS and CCK in those brain regions. These data suggest that peptidergic system in the brain presumably plays an important role in the control of negative schizophrenia.