Animal Model Of Schizophrenia Research Articles

Effects of omega-3 supplementation on interleukin and neurotrophin levels in an animal model of schizophrenia.

New studies suggest that polyunsaturated fatty acids, such as omega-3, may reduce the symptoms of schizophrenia. The present study evaluated the preventive effect of omega-3 on interleukines (IL) and neurotrophin brain-derived neurotrophic factor (BDNF) levels in the brains of young rats subjected to a model of schizophrenia. Treatment was performed over 21 days, starting on the 30th day of rat's life. After 14 days of treatment with omega-3 or vehicle, a concomitant treatment with saline or ketamine (25 mg/kg) was started and maintained until the last day of the experiment. BDNF levels in the rat's prefrontal cortex were decreased at 1 h and 24 h after the last administration of ketamine, whereas the group administered with ketamine and omega-3 showed a decrease in BDNF levels only after 24 h. In contrast, both interventions induced similar responses in levels of IL-1β and IL6. These findings suggest that the similarity of IL-1β and IL6 levels in our experimental groups is due to the mechanism of action of ketamine on the immune system. More studies have to be carried out to explain this pathology. In conclusion, according to previous studies and considering the current study, we could suggest a prophylactic role of omega-3 against the outcome of symptoms associated with schizophrenia.

Ketamine and phencyclidine: the good, the bad and the unexpected.

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.

Inflammational Animal Models for Schizophrenia

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

What We Can Learn From Animal Behavior

In this issue of the Zeitschrift fur Psychologie we have assembled a number of articles and comments that deal with the role of animal behavior in neurobiological and psychological basic research, in behavioral models of psychiatric disorders, and in the treatment of psychiatric patients. In a short review, Schweinfurth and Lang (2015) introduce several behavioral tests, which address symptoms of depression and anxiety and are commonly used in the development of new psychiatric drugs and the exploration of their efficacy. Juckel (2015) describes how inflammational and immunological processes are connected with the pathophysiology of schizophrenia. In his article, he describes how microglia can induce a rarification of synaptic connections in frontal and temporal brain regions. In this context, he introduces promising inflammational animal models for schizophrenia with high validity that can be used to mimic behavioral as well as neurobiological findings in patients. Two articles focus on new molecular pathways that might be highly relevant in the pathophysiology not only of cancer, viral infections, and obstetric complications, but also of affective disorders and schizophrenia. Phosphatidylinositol-3-kinase signaling has shown to be changed in patients with schizophrenia and their first degree relatives. In the article by Lang et al. (2015), a combined data set concerning human genetic, psychopathological, and electrophysiological, and animal neurotransmission data is shown. In conclusion, phosphatidylinositol-3-kinase signaling might have an impact on the pathophysiology of schizophrenia (Lang et al., 2015). Additionally, the regulation of anxiety might be modulated by brain-derived neurotrophic dependent phosphatidylinositide-3-kinase signaling (Leibrock, Hierlmeier, Lang, & Lang, 2015). A behavioral study in mice shows differences in the behavior of gene targeted mice lacking functional Akt isoforms Akt1 (akt1) or Akt3 (akt3) when compared to that of wild type (wt) mice in the open-field test, light/dark transition test, O-maze test, and forced swimming test, which suggests them to be more anxious than their wild type controls (Leibrock et al., 2015). In the article by Bolten (2015), the influence of early stress, maternal nutrition, social stress, and developmental influences is introduced and discussed. In conclusion, this topical issue both reviews concepts, methodology, and application of behavioral animal test approaches to psychological research and carries them further by adding new facets. In addition, the influence of animals on human health is shown in a short Research Spotlight on an animal-assisted intervention for recurrent depression (Schramm, Hediger, & Lang, 2015). Several articles describe how animal behavioral tests can open new research directions and answer new molecular challenges. Furthermore, directions for future work are outlined and critically discussed.

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5′-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed.

A Methionine-Induced Animal Model of Schizophrenia: Face and Predictive Validity.

Background:Modulating the methylation process induces broad biochemical changes, some of which may be involved in schizophrenia. Methylation is in particular central to epigenesis, which is also recognized as a factor in the etiology of schizophrenia. Because methionine administration to patients with schizophrenia has been reported to exacerbate their psychotic symptoms and because mice treated with methionine exhibited social deficits and prepulse inhibition impairment, we investigated whether methionine administration could lead to behavioral changes that reflect schizophrenic symptoms in mice.Methods: l-Methionine was administered to mice twice a day for 7 days.Results:We found that this treatment induces behavioral responses that reflect the 3 types of schizophrenia-like symptoms (positive, negative, or cognitive deficits) as monitored in a battery of behavioral assays (locomotion, stereotypy, social interaction, forced swimming, prepulse inhibition, novel object recognition, and inhibitory avoidance). Moreover, these responses were differentially reversed by typical haloperidol and atypical clozapine antipsychotics in ways that parallel their effects in schizophrenics.Conclusion:We thus propose the l-methionine treatment as an animal model recapitulating several symptoms of schizophrenia. We have established the face and predictive validity for this model. Our model relies on an essential natural amino acid and on an intervention that is relatively simple and time effective and may offer an additional tool for assessing novel antipsychotics.

Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Cortical–Subcortical Networks in Humans: Evidence From Resting-State Magnetoencephalography-Recordings

Hypofunctioning of the N-methyl-D-aspartate receptor (NMDA-R) has been prominently implicated in the pathophysiology of schizophrenia (ScZ). The current study tested the effects of ketamine, a dissociative anesthetic and NMDA-R antagonist, on resting-state activity recorded with magnetoencephalography (MEG) in healthy volunteers. In a single-blind cross-over design, each participant (n = 12) received, on 2 different sessions, a subanesthetic dose of S-ketamine (0.006 mg/Kg) and saline injection. MEG-data were analyzed at sensor- and source-level in the beta (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In addition, connectivity analysis at source-level was performed using transfer entropy (TE). Ketamine increased gamma-power while beta-band activity was decreased. Specifically, elevated 30-90 Hz activity was pronounced in subcortical (thalamus and hippocampus) and cortical (frontal and temporal cortex) regions, whilst reductions in beta-band power were localized to the precuneus, cerebellum, anterior cingulate, temporal and visual cortex. TE analysis demonstrated increased information transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the pronounced dysregulation of high-frequency oscillations following the inhibition of NMDA-R in animal models of ScZ as well as with evidence from electroencephalogram-data in ScZ-patients and increased functional connectivity during early illness stages. Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits.

Corrigendum to “Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia” [Brain Behav. Immun. 38 (2014) 175–184

Corrigendum to “Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia” [Brain Behav. Immun. 38 (2014) 175–184

Brain in flames - animal models of psychosis: utility and limitations.

The neurodevelopmental hypothesis of schizophrenia posits that schizophrenia is a psychopathological condition resulting from aberrations in neurodevelopmental processes caused by a combination of environmental and genetic factors which proceed long before the onset of clinical symptoms. Many studies discuss an immunological component in the onset and progression of schizophrenia. We here review studies utilizing animal models of schizophrenia with manipulations of genetic, pharmacologic, and immunological origin. We focus on the immunological component to bridge the studies in terms of evaluation and treatment options of negative, positive, and cognitive symptoms. Throughout the review we link certain aspects of each model to the situation in human schizophrenic patients. In conclusion we suggest a combination of existing models to better represent the human situation. Moreover, we emphasize that animal models represent defined single or multiple symptoms or hallmarks of a given disease.

D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial

Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620. We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. National Institutes of Health.

Effects of the selective 5-HT7 receptor antagonist SB-269970 on premature responding in the five-choice serial reaction time test in rats

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-d-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail.The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed.MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5mg/kg) and SB-269970 (1mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze.The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.

Glutamate Decarboxylase 67 Deficiency in a Subset of GABAergic Neurons Induces Schizophrenia-Related Phenotypes.

Decreased expression of the GABA synthetic enzyme glutamate decarboxylase 67 (GAD67) in a subset of GABAergic neurons, including parvalbumin (PV)-expressing neurons, has been observed in postmortem brain studies of schizophrenics and in animal models of schizophrenia. However, it is unclear whether and how the perturbations of GAD67-mediated GABA synthesis and signaling contribute to the pathogenesis of schizophrenia. To address this issue, we generated the mice lacking GAD67 primarily in PV neurons and characterized them with focus on schizophrenia-related parameters. We found that heterozygous mutant mice exhibited schizophrenia-related behavioral abnormalities such as deficits in prepulse inhibition, MK-801 sensitivity, and social memory. Furthermore, we observed reduced inhibitory synaptic transmission, altered properties of NMDA receptor-mediated synaptic responses in pyramidal neurons, and increased spine density in hippocampal CA1 apical dendrites, suggesting a possible link between GAD67 deficiency and disturbed glutamatergic excitatory synaptic functions in schizophrenia. Thus, our results indicate that the mice heterozygous for GAD67 deficiency primarily in PV neurons share several neurochemical and behavioral abnormalities with schizophrenia, offering a novel tool for addressing the underlying pathophysiology of schizophrenia.

Altered basolateral amygdala encoding in an animal model of schizophrenia.

It has been proposed that schizophrenia results, in part, from the inappropriate or spurious attribution of salience to cues in the environment. We have recently reported neural correlates of salience in the basolateral amygdala (ABL) of rats during learning in an odor-guided discrimination task. Here we tested whether this dopamine-dependent salience signal is altered in rats with neonatal ventral hippocampal lesions (NVHLs), a rodent model of schizophrenia. We found that ABL signals related to violations in reward prediction were only mildly affected by NVHL; however, neurons in rats with NVHLs showed significantly stronger selectivity during odor sampling, particularly for the more salient large-reward cue. The elevated cue-evoked activity in NVHL rats was correlated with heightened orienting behavior and also with changes in firing to the shifts in reward, suggesting that it reflected abnormal signaling of the large reward-predicting cue's salience. These results are broadly consistent with the proposal that schizophrenics suffer from enhanced signaling of salience.

Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia.

Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17. Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot. VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM. Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood.

Aberrant high frequency oscillations recorded in the rat nucleus accumbens in the methylazoxymethanol acetate neurodevelopmental model of schizophrenia.

Altered activity of the nucleus accumbens (NAc) is thought to be a core feature of schizophrenia and animal models of the disease. Abnormal high frequency oscillations (HFO) in the rat NAc have been associated with pharmacological models of schizophrenia, in particular the N-methyl-d-aspartate receptor (NMDAR) hypofunction model. Here, we tested the hypothesis that abnormal HFO are also associated with a neurodevelopmental rat model. Using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM) we obtained the offspring MAM rats. Adult MAM and Sham rats were implanted with electrodes, for local field potential recordings, in the NAc. Spontaneous HFO (spHFO) in MAM rats were characterized by increased power and frequency relative to Sham rats. MK801 dose-dependently increased the power of HFO in both groups. However, the dose-dependent increase in HFO frequency found in Sham rats was occluded in MAM rats. The antipsychotic compound, clozapine reduced the frequency of HFO which was similar in both MAM and Sham rats. Further, HFO were modulated in a similar manner by delta oscillations in both MAM and Sham rats. Together these findings suggest that increased HFO frequency represents an important feature in certain animal models of schizophrenia. These findings support the hypothesis that altered functioning of the NAc is a core feature in animal models of schizophrenia.

Examining the Consequences of Pre‐natal Exposure to Stress in the Behavior of Adult Offspring

Stress has been associated to the development of cognitive and other behavioral deficits. Moreover, it is well established that stress, during, and after a pregnancy, has multiple quantifiable effects in the overall development of the offspring. Our lab is interested in studying the predisposition to psychosis on the offspring upon maternal induction of stress together with N-methyl-D-aspartate (NMDA) receptor hypofunction during pregnancy. Thus, our first step is determining psychotic-like phenotypes in a group subjected solely to stress during pregnancy. Towards this end, mice were randomly divided into 2 groups: control and stressed. Males and females were paired to induce pregnancy. Five days after confirmation of a vaginal plug; a stress induction procedure was randomly administered on the experimental group. This procedure was continued until birth, after which the pups were allowed to be nurtured for 21 days. Pups were subsequently tested for behavioral abnormalities related to cognition, anxiety, sensorimotor gating, etc. Our results indicate a significant increase in anxiety-related behaviors in both the pups and mothers of the experimental group. Incidence of depression was also significantly increased in the experimental group compared with the control. Taken together, our findings so far suggest that prenatal stress exposure significantly changes several facets of adult mice behavior. Interestingly, the behaviors that are altered have been used to validate animal models of schizophrenia, suggesting that this experimental protocol will be useful to compare with additional groups showing additional dysfunction of the NMDA receptor.

Animal Models of Schizophrenia with a Focus on Models Targeting NMDA Receptors

Animal Models of Schizophrenia with a Focus on Models Targeting NMDA Receptors

Effect of sepsis on behavioral changes on the ketamine-induced animal model of schizophrenia.

This study aimed to evaluate the effect of sepsis on behavioral changes on the ketamine-induced animal model of schizophrenia. Male Wistar rats underwent Cecal Ligation and Perporation (CLP) with "basic support" or were sham-operated. After 30 days, the animals were submitted to a model of schizophrenia by injection of Ketamine. The behavior tests were performed after 30 min of the injection of Ketamine or saline. Ketamine in doses of 15 and 25mg/kg increased locomotor activity, latency to first contact in the social interaction and stereotyped behavior. Some changes caused by sepsis may be associated with a predisposition to develop schizophrenia in the animal model.

Role of Spreading Depression On Memory Consolidation in Developmental Animal Model of Schizophrenia

Background Schizophrenia is a complex disorder, characterized by both genetic and environmental factors and their interactions. Post weaning social isolation (SI) has been proposed as a model of Schizophrenia. Glutamate hypothesis in schizophrenia produce analogous symptoms. In this regards, reduction in NMDA receptor activity has been hypothesized for induction of schizophrenia in clinical studies. Furthermore, NMDA receptors activation play role in various neurodegenerative diseases including phenomenon of spreading depression (SD). SD plays a pivotal role in glutamate release and its action on the NMDA receptor. Method and material In the present study 24Wistar juvenile rats (65-80 gr) were used. Animals were classified in three groups as SD treated with Social isolation, social isolation, and sham groups. SI was induced by six week post weaning social isolation of puppies, which followed by four consecutive weeks SD induction in SD-social isolation group. Prepulse inhibition (PPI) test and passive avoidance by shuttle box test have been done at the end of experiment. Results Our result from behavioral test suggested that SD induction during for week after six week social isolation may be able to help to ameliorate schizophrenia symptoms. Significant changes in cognition tests were seen in SD induced group in comparison with social isolation group. Conclusion data from present study revealed that glutamate level in extracellular space which followed by NMDA receptor activation as well as its expression following SD induction perhaps decrease some neurological characteristics of schizophrenia, which could reveal NMDA protective role on schizophrenic patient.

Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?

Group II metabotropic glutamate receptor (mGluR2/3) agonists once showed promise as non-dopaminergic antipsychotic drugs because of their efficacy in alleviating symptoms of schizophrenia (SZ) in both animal models and human patients. However, the recent failure of Phase III clinical trials dealt a huge blow to the scientific community and the aftershock of the setback in mGluR2/3 research can be felt everywhere from grant support and laboratory studies to paper publication. An immediate question raised is whether mGluR2/3 is still a promising therapeutic target for schizophrenia. Answering this question is not easy, but apparently a new strategy is needed. This article provides a focused review of literature on the study of mGluR2/3 agonists, especially on mGluR2/3 agonists' mechanism of action and efficacy in both normal conditions and animal models of SZ, as well as clinical studies in human patients with the disease. We argue that the cellular and molecular actions of mGluR2/3 agonists, the distinct roles between mGluR2 and mGluR3, as well as their effects on different stages of the disease and different subpopulations of patients, remain incompletely studied. Until the mechanisms associated with mGluR2/3 are clearly elucidated and all treatment options are tested, it would be a great mistake to terminate the study of mGluR2/3 as a therapeutic target for schizophrenia. This review will thus shed light on the comprehensive features of the translational potential mGluR2/3 agonists as well as the need for further research into the more selective activation of mGluR2.