Schizophrenia-like Phenotype Research Articles

Prenatal Exposure to MAM Impairs mPFC and Hippocampal Inhibitory Function in Mice during Adolescence and Adulthood.

Neurodevelopmental abnormalities are considered to be one of the important causes of schizophrenia. The offspring of methylazoxymethanol acetate (MAM)-exposed mice are recognized for the dysregulation of neurodevelopment and are well-characterized with schizophrenia-like phenotypes. However, the inhibition-related properties of the medial prefrontal cortex (mPFC) and hippocampus throughout adolescence and adulthood have not been systematically elucidated. In this study, both 10 and 15 mg/kg MAM-exposed mice exhibited schizophrenia-related phenotypes in both adolescence and adulthood, including spontaneous locomotion hyperactivity and deficits in prepulse inhibition. We observed that there was an obvious parvalbumin (PV) loss in the mPFC and hippocampus of MAM-exposed mice, extending from adolescence to adulthood. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons at mPFC and hippocampus was significantly dampened in the 10 and 15 mg/kg MAM-exposed mice. Furthermore, the firing rate of putative pyramidal neurons in mPFC and hippocampus was increased, while that of putative inhibitory neurons was decreased during both adolescence and adulthood. In conclusion, PV loss in mPFC and hippocampus of MAM-exposed mice may contribute to the impaired inhibitory function leading to the attenuation of inhibition in the brain both in vitro and in vivo.

Systematic review and meta-analysis on the effects of chronic peri-adolescent cannabinoid exposure on schizophrenia-like behaviour in rodents.

The link between cannabis use and schizophrenia is well-established in epidemiological studies, especially among adolescents with early-onset use. However, this association in rodent models is less clear. This meta-analysis examined the effects of adolescent cannabinoid exposure on distinct schizophrenia-like behaviours in rodents and how experimental variations influence outcomes. Following a pre-registered protocol (CRD42022338761), we searched PubMed, Ovid Medline, Embse and APA PsychInfo for English-language original studies until May 2024. We synthesised data from experiments on schizophrenia-like behaviour in rats and mice after repeated peri-pubertal (onset between P23-P45) cannabinoid exposure. Risk of bias was assessed using the SYRCLE's tool. We included 359 experiments from 108 articles across 9 behavioural tests. We found meta-analytic evidence supporting that CB1R agonists, both natural and synthetic, elicited broad schizophrenia-like behavioural alterations, including impaired working memory [g = -0.56; (CI: -0.93, -0.18)], novel object recognition [g = -0.66; (CI: -0.97, -0.35)], novel object location recognition [g = -0.70; (CI: -1.07, -0.33]), social novelty preference [g = -0.52; (CI: -0.93, -0.11)], social motivation [g = -0.21; (CI: -0.42, -0.00)], pre-pulse inhibition [g = -0.43; (CI: -0.76, -0.10)], and sucrose preference [g = -0.87; (CI: -1.46, -0.27)]. By contrast, effects on novelty-induced locomotion were negligible. Subgroup analyses revealed similar effects across sexes and species. Substantial variance in the protocols and moderate-to-high heterogeneity in behavioural outcomes were observed. We found CBD may enhance fear memory recall, but data was limited. This is the first meta-analysis to comprehensively assess the link between cannabinoids and schizophrenia-like behaviours in rodents. Our results support epidemiological links between early cannabis use and schizophrenia-like phenotypes, confirming the utility of animal models. Standardising protocols will optimise models to strengthen reproducibility and comparisons, our work provides a framework for refining rodent models to elucidate biological pathways linking cannabis and schizophrenia.

Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice

Current approaches to the treatment of schizophrenia have mainly focused on the protein-coding part of the genome; in this context, the roles of microRNAs have received less attention. In the present study, we analyze the microRNAome in the blood and postmortem brains of schizophrenia patients, showing that the expression of miR-99b-5p is downregulated in both the prefrontal cortex and blood of patients. Lowering the amount of miR-99b-5p in mice leads to both schizophrenia-like phenotypes and inflammatory processes that are linked to synaptic pruning in microglia. The microglial miR-99b-5p-supressed inflammatory response requires Z-DNA binding protein 1 (Zbp1), which we identify as a novel miR-99b-5p target. Antisense oligonucleotides against Zbp1 ameliorate the pathological effects of miR-99b-5p inhibition. Our findings indicate that a novel miR-99b-5p-Zbp1 pathway in microglia might contribute to the pathogenesis of schizophrenia.

Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates.

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment.

What have genetic studies of rare sequence variants taught us about the aetiology of schizophrenia?

With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A , CACNA1G , CUL1 , GRIA3 , GRIN2A , HERC1 , RB1CC1 , SP4 , TRIO , XPO7 , and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.

Cannabinoid CB2 receptors and hypersensitivity to methamphetamine: Vulnerability to schizophrenia

The human cannabinoid receptor 2 (CB2R) gene CNR2 has been associated with schizophrenia development. Inbred mice treated with the CB2R inverse agonist AM630 and challenged with methamphetamine (MAP) showed reduced prepulse inhibition (%PPI) response and locomotor hyperactivity, both behavioral measures in rodents that correlate with psychosis. Mice lacking CB2R on striatal dopaminergic neurons exhibit a hyperdopaminergic tone and a hyperactivity phenotype. Hyperdopaminergia plays a role in the etiology of schizophrenia. This study aimed to determine the direct role of CB2R, heterozygous Cnr2 gene knockout (Het) mice treated with MAP to induce behavioral sensitivity mimicking a schizophrenia-like human phenotype. Additionally, the study aims to explore the unique modulation of dopamine activity by neuronal CB2R. Conditional knockout DAT-Cnr2−/− mice were evaluated in response to MAP treatments for this purpose. Sensorimotor gating deficits in DAT-Cnr2−/− mice were also evaluated. Het mice developed reverse tolerance (RT) to MAP-enhanced locomotor activity, and RT reduced the %PPI compared to wild-type (WT) mice. DAT-Cnr2−/− mice showed an increased sensitivity to stereotypical behavior induced by MAP and developed RT to MAP. DAT-Cnr2−/− mice exhibit a reduction in %PPI and alter social interaction, another core symptom of schizophrenia. These results demonstrate that there is an interaction between neuronal CB2R and MAP treatment, which increases the risk of schizophrenia-like behavior in this mouse model. This finding provides evidence for further studies targeting CB2R as a potential schizophrenia therapy.

Congenital blindness does not protect against a schizophrenia-related phenotype in rodents.

In 1950, Drs. Chevigny and Braverman authored a book about people's attitudes and prejudices toward the blind, noting that out of the thousands of schizophrenia patients they and others had treated, not one was blind. This led some to the intriguing hypothesis that congenital blindness may provide protection against schizophrenia. In this study, we directly examined whether congenital blindness protects against a schizophrenia-related phenotype in the methylazoxymethanol acetate (MAM) rodent model. Enucleation surgeries were performed on pups of MAM- or saline-treated rats on post-natal day 10. Once pups reached adulthood, male and female rats were evaluated for schizophrenia-like phenotypes using behavioral and electrophysiological measures. Consistent with previous work, MAM-treated rats display elevated dopamine neuron population activity, deficits in pre-pulse inhibition of startle, and hypersensitivity to psychomotor stimulants. Blindness did not protect against any of the MAM-induced phenotypes. Surprisingly, blindness in saline-treated rats caused changes in behavior and dopamine neuron activity. To examine the circadian rhythms of enucleated rats, we performed non-invasive measurements of corticosterone, a steroid hormone known to vary across the light/dark period, revealing blind rats display aberrant (non-cycling) corticosterone levels. Alterations in dopamine neuron activity and associated behaviors observed in blind rats are likely secondary to aberrant circadian regulation. This is the first preclinical study examining whether congenital blindness protects against a schizophrenia-like phenotype. While support of this hypothesis would have led to novel avenues of research and potential novel therapies, the results of current study suggest that blindness does not protect against schizophrenia.

Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia.

Glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms. This theory arose from the observation that administration of NMDAR antagonists, which are compounds that inhibit NMDAR activity, reproduces behavioural and molecular schizophrenia-like phenotypes, including hallucinations, delusions and cognitive impairments in healthy humans and animal models. However, the role of specific NMDAR subunits in these schizophrenia-relevant phenotypes is largely unknown. Mounting evidence implicates the GluN2D subunit of NMDAR in some of these symptoms and pathology. Firstly, genetic and post-mortem studies show changes in the GluN2D subunit in people with schizophrenia. Secondly, the psychosis-inducing effects of NMDAR antagonists are blunted in GluN2D-knockout mice, suggesting that the GluN2D subunit mediates NMDAR-antagonist-induced psychotomimetic effects. Thirdly, in the mature brain, the GluN2D subunit is relatively enriched in parvalbumin (PV)-containing interneurons, a cell type hypothesized to underlie the cognitive symptoms of schizophrenia. Lastly, the GluN2D subunit is widely and abundantly expressed early in development, which could be of importance considering schizophrenia is a disorder that has its origins in early neurodevelopment. The limitations of currently available therapies warrant further research into novel therapeutic targets such as the GluN2D subunit, which may help us better understand underlying disease mechanisms and develop novel and more effective treatment options.

The suitability of zebrafish (danio rerio) as an optimal organism to further investigate the associated schizophrenia-like phenotype

IntroductionZebrafish (Danio rerio) has evolved over the years as a preferred organism due to its vast repertoire in research fields that mimic a targeted phenotype, particularly behavioral typologies and specific attributes comparable to murine models and relatively high homology with humans. Considering this consideration, different pharmacological treatments have been tested and proven that under different concentrations may trigger schizophrenia (SCZ)-like symptoms.ObjectivesStarting from the actual stage of knowledge according to which agents used as N-methyl-D-aspartate (NMDA) inhibitors (MK-801, ketamine, and phencyclidine) alongside psychedelic (mescaline, lysergic acid diethylamide), psychoactive substances (amphetamine), and non- and essential amino acids (proline and methionine), we aimed to reunite and review all existing evidence. This approach may offer an updated and critical overview regarding the possible future directions surrounding these compounds regarding the pharmaco-dynamics/kinetics.MethodsTo ensure the coverage of all relevant literature, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) per combinations of keywords: “schizophrenia” with “MK-801”, “ketamine”, “phencyclidine”, “mescaline”, “lysergic acid diethylamide”, “amphetamine”, “proline”, “methionine”, and “zebrafish”. Eligible studies had to be “research article(s)” written in English.ResultsA total of n = 246 studies were returned during the established interval (2010 – 2022). Precisely, n = 16 were identified in PubMed/Medline, n = 16 in ISI Web of Knowledge, n = 17 in Scopus, and n = 197 in ScienceDirect per database. If taken per year, n = 13 were published in 2010, n = 12 in 2011, n = 15 in 2012, n = 24 in 2013, n = 21 in 2014, n = 21 in 2015, n = 32 in 2016, n = 8 in 2017, n = 12 in 2018, n = 9 in 2019, n = 17 in 2020, n = 34 in 2021, and n = 28 in 2022. Depending on the combination of keywords, we had the following situation: n = 65 for “schizophrenia+MK-801+zebrafish”, n = 42 for “schizophrenia+ketamine+zebrafish”, n = 21 for “schizophrenia+phencyclidine+zebrafish”, n = 4 for “schizophrenia+mescaline+zebrafish”, n = 5 for “schizophrenia+lysergic acid diethylamide+zebrafish”, n = 36 for “schizophrenia+amphetamine+zebrafish”, n = 37 for “schizophrenia+proline+zebrafish”, n = 36 for “schizophrenia+ methionine+zebrafish”.ConclusionsThere can be seen an uprising trend in the current literature of studies focused on the administration of MK-801, ketamine, amphetamine, proline, methionine, and phencyclidine aiming to trigger SCZ-like symptoms as opposed to mescaline and lysergic acid diethylamide. Most of the data is contradicting, with either a decrease/increase in behavior (locomotion, aggression, sociability, circling behavior, and memory deficits), which is why additional studies are mandatory.Disclosure of InterestNone Declared

Histamine H2 receptor deficit in glutamatergic neurons contributes to the pathogenesis of schizophrenia

Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H1 receptor; however, the role of the H2receptor (H2R) is not quite clear, especially in schizophrenia. Here, we found that expression of H2R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H2R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 fl/fl) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in invivo electrophysiological tests. Selective knockdown of H2R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H2R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H2R overexpression in glutamatergic neurons or H2R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H2R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H2R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H2R in the brain, especially in glutamatergic neurons.

Effects of Transient Administration of the NMDA Receptor Antagonist MK-801 in Drosophila melanogaster Activity, Sleep, and Negative Geotaxis.

MK-801, also called dizocilpine, is an N-methyl-D-aspartate (NMDA) receptor antagonist widely used in animal research to model schizophrenia-like phenotypes. Although its effects in rodents are well characterised, little is known about the outcomes of this drug in other organisms. In this study, we characterise the effects of MK-801 on the locomotion, sleep, and negative geotaxis of the fruit fly Drosophila melanogaster. We observed that acute (24 h) and chronic (7 days) administration of MK-801 enhanced negative geotaxis activity in the forced climbing assay for all tested concentrations (0.15 mM, 0.3 mM, and 0.6 mM). Moreover, acute administration, but not chronic, increased the flies' locomotion in a dose-dependent matter. Finally, average sleep duration was not affected by any concentration or administration protocol. Our results indicate that acute MK-801 could be used to model hyperactivity phenotypes in Drosophila melanogaster. Overall, this study provides further evidence that the NMDA receptor system is functionally conserved in flies, suggesting the usefulness of this model to investigate several phenotypes as a complement and replacement of the rodent models within drug discovery.

Nicotinamide reverses deficits in puberty-born neurons and cognitive function after maternal separation

BackgroundEarly life stress (ELS) is associated with the development of schizophrenia later in life. The hippocampus develops significantly during childhood and is extremely reactive to stress. In rodent models, ELS can induce neuroinflammation, hippocampal neuronal loss, and schizophrenia-like behavior. While nicotinamide (NAM) can inhibit microglial inflammation, it is unknown whether NAM treatment during adolescence reduces hippocampal neuronal loss and abnormal behaviors induced by ELS.MethodsTwenty-four hours of maternal separation (MS) of Wistar rat pups on post-natal day (PND)9 was used as an ELS. On PND35, animals received a single intraperitoneal injection of BrdU to label dividing neurons and were given NAM from PND35 to PND65. Behavioral testing was performed. Western blotting and immunofluorescence staining were used to detect nicotinamide adenine dinucleotide (NAD+)/Sirtuin3 (Sirt3)/superoxide dismutase 2 (SOD2) pathway-related proteins.ResultsCompared with controls, only MS animals in the adult stage (PND56–65) but not the adolescent stage (PND31–40) exhibited pre-pulse inhibition deficits and cognitive impairments mimicking schizophrenia symptoms. MS decreased the survival and activity of puberty-born neurons and hippocampal NAD+ and Sirt3 expression in adulthood. These observations were related to an increase in acetylated SOD2, microglial activation, and significant increases in pro-inflammatory IL-1β, TNF-α, and IL-6 expression. All the effects of MS at PND9 were reversed by administering NAM in adolescence (PND35–65).ConclusionsMS may lead to schizophrenia-like phenotypes and persistent hippocampal abnormalities. NAM may be a safe and effective treatment in adolescence to restore normal hippocampal function and prevent or ameliorate schizophrenia-like behavior.

Comprehensive metabolomic characterization of the hippocampus in a ketamine mouse model of schizophrenia

Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate receptors (NMDARs). We have shown that ketamine can induce cognitive impairments and schizophrenia-like symptoms in mice. However, the detailed metabolic profile changes in the progression of ketamine-induced schizophrenia-like symptoms are still not fully elucidated. In this study, an ultra-performance liquid chromatography-Q-Exactive hybrid quadrupole-Orbitrap mass spectrometry-based untargeted hippocampus high-throughput metabolomics method was first performed to screen for potential biomarkers in a schizophrenia-like state in a chronically administered ketamine-induced mouse model. Our results identified that the amino acid and energy metabolism pathways were significantly affected in mouse models of ketamine-induced schizophrenia. The detailed amino acid profiles were subsequently quantified in the hippocampus. The results showed that ketamine dramatically decreased the Lys, Gly, and Ser levels while significantly increasing the Gln level and relative Glu-to-GABA ratio. Our study suggested that Gln, Gly and Ser metabolism disturbances might be involved in ketamine-induced schizophrenia-like phenotypes. This research offers a fresh viewpoint for creating new neuroleptic medications and contributes to understanding the mechanisms underlying ketamine-induced schizophrenia.

Astrocyte Activation, but not Microglia, Is Associated with the Experimental Mouse Model of Schizophrenia Induced by Chronic Ketamine.

Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. Many experimental studies have shown that ketamine can induce cognitive impairments and schizophrenia-like symptoms. While much data have demonstrated that glial cells are associated with the pathophysiology of psychiatric disorders, including schizophrenia, the response of glial cells to ketamine and its significance to schizophrenia are not clear. The present study was intended to explore whether chronic ketamine treatment would induce behavioral and glial changes in mice. First, ketamine was used to stimulate behavioral abnormalities similar to schizophrenia evaluated by the open field test, elevated plus-maze test, Y maze test, novel object recognition test, and tail suspension test. Secondly, histopathology and Nissl staining were performed. Meanwhile, immunofluorescence was used to evaluate the expression levels of IBA-1 (a microglial marker) and GFAP (an astrocyte marker) in the mouse hippocampus for any change. Then, ELISA was used to analyze proinflammatory cytokine levels for any change. Our results showed that ketamine (25mg/kg, i.p., qid, 12days) induced anxiety, recognition deficits, and neuronal injury in the hippocampus. Moreover, chronic ketamine treatment enhanced GFAP expression in CA1 and DG regions of the hippocampus but did not influence the expression of IBA-1. Ketamine also increased the levels of IL-1β, IL-6, and TNF-α in the mouse hippocampus. Our study created a new procedure for ketamine administration, which successfully induce negative symptoms and cognitive-behavioral defects in schizophrenia by chronic ketamine. This study furtherrevealed that an increase in astrocytosis, but not microglia, is associated with the mouse model of schizophrenia caused by ketamine. In summary, hippocampal astrocytes may be involved in the pathophysiology of ketamine-induced schizophrenia-like phenotypes through reactive transformation and regulation of neuroinflammation.

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study.

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment.

The 14-3-3 Protein Family and Schizophrenia.

Schizophrenia is a debilitating mental disorder that affects approximately 1% of the world population, yet the disorder is not very well understood. The genetics of schizophrenia is very heterogenous, making it hard to pinpoint specific alterations that may cause the disorder. However, there is growing evidence from human studies suggesting a link between alterations in the 14-3-3 family and schizophrenia. The 14-3-3 proteins are abundantly expressed in the brain and are involved in many important cellular processes. Knockout of 14-3-3 proteins in mice has been shown to cause molecular, structural, and behavioral alterations associated with schizophrenia. Thus, 14-3-3 animal models allow for further exploration of the relationship between 14-3-3 and schizophrenia as well as the study of schizophrenia pathology. This review considers evidence from both human and animal model studies that implicate the 14-3-3 family in schizophrenia. In addition, possible mechanisms by which alterations in 14-3-3 proteins may contribute to schizophrenia-like phenotypes such as dopaminergic, glutamatergic, and cytoskeletal dysregulations are discussed.

Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia.

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Oxytocin attenuates schizophrenia-like reduced sensorimotor gating in outbred and inbred rats in line with strain differences in CD38 gene expression

Prepulse inhibition (PPI) of the startle response is a measure of sensorimotor gating that is impaired in many clinical conditions, including schizophrenia. The inbred Roman high-avoidance (RHA) rats, compared to their low-avoidance (RLA) counterparts, show distinct schizophrenia-like phenotypes, such as spontaneous deficits in PPI accompanied by decreased medial prefrontal cortex (mPFC) activity and volume. Schizophrenia-like deficits are usually attenuated by antipsychotic drugs, but these drugs often produce severe side effects. In order to reduce these side effects, the neuropeptide oxytocin has been proposed as an alternative natural antipsychotic for schizophrenia. Here, we examined the effects of peripheral oxytocin administration (saline, 0.04, and 0.2 mg/kg) on PPI in the RHA vs. RLA rats, as well as in the outbred heterogeneous stock (HS) rats. Our results showed that oxytocin increased PPI in the HS rats and attenuated PPI deficits in the RHA rats, but it did not significantly affect PPI in the RLAs. To explore whether these divergent effects were associated with differences in oxytocinergic mechanisms, we analyzed gene expression of the oxytocin receptor (OXTR) and the regulator of oxytocin release (CD38) in the mPFC of the Roman rats. Consistent with the differential oxytocin effects on PPI (RHA > RLA), constitutive CD38 expression was reduced in the RHA rats compared to the RLAs, while oxytocin administration increased OXTR expression in both strains. Overall, the present work reveals that oxytocin administration shows antipsychotic-like effects on PPI in outbred and inbred rats, and it suggests that these effects may be related to basal differences in oxytocin-mediated mechanisms in the mPFC.

Taurine prevents MK-801-induced shoal dispersion and altered cortisol responses in zebrafish

Schizophrenia is a chronic neuropsychiatric disorder characterized by a shortened lifespan and significant impaired social and vocational functioning. Schizophrenic patients can present hypothalamic-pituitary-adrenal (HPA) axis dysfunctions and cortisol dysregulation, which play an important role on the etiology onset, exacerbation, and relapsing of symptoms. Based on its intrinsic neuroprotective properties, taurine is considered a promising substance with beneficial role on various brain disorders, including schizophrenia. Here, we evaluated the effects of taurine on shoaling behavior and whole-body cortisol levels in zebrafish treated with dizocilpine (MK-801), which elicits schizophrenia-like phenotypes in animal models. Briefly, zebrafish shoals (4 fish per shoal) were exposed to dechlorinated water or taurine (42, 150, or 400 mg/L) for 60 min. Then, saline (PBS, pH 7.4 or 2.0 mg/kg MK-801) were intraperitoneally injected and zebrafish behavior was recorded 15 min later. In general, MK-801 disrupted shoaling behavior and reduced whole-body cortisol levels in zebrafish. All taurine pretreatments prevented MK-801-induced increase in shoal area, while 400 mg/L taurine prevented the MK-801-induced alterations in neuroendocrine responses. Moreover, all taurine-pretreated groups showed increased geotaxis, supporting a modulatory role in the overall dispersion pattern of the shoal. Collectively, our novel findings show a potential protective effect of taurine on MK-801-induced shoal dispersion and altered neuroendocrine responses, fostering the use of zebrafish models to assess schizophrenia-like phenotypes.

Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats.

Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder.