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Cajal–Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro–caudal and medio–lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.

Schizophrenia is highly heritable and aggregating in families, but genetics alone does not exclusively explain the pathogenesis. Many risk factors, including childhood trauma, viral infections, migration, and the use of cannabis, are associated with schizophrenia. Adolescence seems to be the critical period where symptoms of the disease manifest. This work focuses on studying an epigenetic regulatory mechanism (the role of DNA methylation) and its interaction with mRNA expression during development, with a particular emphasis on adolescence. The presumptions regarding the role of aberrant neurodevelopment in schizophrenia were tested in the Methyl-Azoxy-Methanol (MAM) animal model. MAM treatment induces neurodevelopmental disruptions and behavioral deficits in off-springs of the treated animals reminiscent of those observed in schizophrenia and is thus considered a promising model for studying this pathology. On a gestational day-17, adult pregnant rats were treated with the antimitotic agent MAM. Experimental animals were divided into groups and subgroups according to substance treatment (MAM and vehicle agent [Sham]) and age of analysis (pre-adolescent and post-adolescent). Methylation and mRNA expression analysis of four candidate genes, which are often implicated in schizophrenia, with special emphasis on the Dopamine hypothesis i.e., Dopamine receptor D2 (Drd2), and the “co-factors” Disrupted in schizophrenia 1 (DISC1), Synaptophysin (Syp), and Dystrobrevin-binding protein 1 (Dtnbp1), was performed in the Gyrus cingulum (CING) and prefrontal cortex (PFC). Data were analyzed to observe the effect of substance treatment between groups and the impact of adolescence within-group. We found reduced pre-adolescent expression levels of Drd2 in both brain areas under the application of MAM. The “co-factor genes” did not show high deviations in mRNA expression levels but high alterations of methylation rates under the application of MAM (up to ~20%), which diminished in the further time course, reaching a comparable level like in Sham control animals after adolescence. The pre-adolescent reduction in DRD2 expression might be interpreted as downregulation of the receptor due to hyperdopaminergic signaling from the ventral tegmental area (VTA), eventually even to both investigated brain regions. The notable alterations of methylation rates in the three analyzed co-factor genes might be interpreted as attempt to compensate for the altered dopaminergic neurotransmission.

The growth hormone secretagogue receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor (GPCR) endowed with a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to WT littermate rats: (1) as freely behaving animals and (2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fedGhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats . In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better body weight and glycemia. Importantly, prior to fat accumulation, male GhsrM/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2: acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof for the concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

Background Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer’s disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. Methods We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats. Results Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued fear conditioning training or tone reexposure. Conclusions These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.

The Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to wild-type littermate rats 1) as freely behaving animals using an automated system to monitor simultaneously energy intake and expenditure, respiratory exchanges and voluntary activity and 2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fed GhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better their body weight and glycemia. Finally, prior to fat accumulation GhsrM/M rats showed shifted fuel preference towards carbohydrates utilization without alterations of energy intake, energy expenditure or physical activity. Overall, the present study provides proof of concept that shifted GHSR signaling can operate a specific alteration in nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

The OTX2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, which projects to limbic structures controlling complex behaviors. OTX2 is also produced in choroid plexus epithelium, from which it is secreted into cerebrospinal fluid and transferred to limbic structure parvalbumin interneurons. Previously, adult male mice subjected to early-life stress were found susceptible to anxiety-like behaviors, with accompanying OTX2 expression changes in ventral tegmental area or choroid plexus. Here, we investigated the consequences of reduced OTX2 levels in Otx2 heterozygote mice, as well as in Otx2

The OTX2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, which projects to limbic structures controlling complex behaviors. OTX2 is also produced in choroid plexus epithelium, from which it is secreted into cerebrospinal fluid and transferred to limbic structure parvalbumin interneurons. Previously, adult male mice subjected to early-life stress were found susceptible to anxiety-like behaviors, with accompanying OTX2 expression changes in ventral tegmental area or choroid plexus. Here, we investigated the consequences of reduced OTX2 levels in Otx2 heterozygote mice, as well as in Otx2+/AA and scFvOtx2tg/0 mouse models for decreasing OTX2 transfer from choroid plexus to parvalbumin interneurons. Both male and female adult mice show anxiolysis-like phenotypes in all three models. In Otx2 heterozygote mice, we observed no changes in dopaminergic neuron numbers and morphology in ventral tegmental area, nor in their metabolic output and projections to target structures. However, we found reduced expression of parvalbumin in medial prefrontal cortex, which could be rescued in part by adult overexpression of Otx2 specifically in choroid plexus, resulting in increased anxiety-like behavior. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of anxiety-related phenotypes in the mouse.

During cerebral development, adolescence is a critical phase in which the endocannabinoid system plays an important role in regulating various neurotransmitters. Moreover, evidence from both human and animal studies suggests that chronic cannabinoid exposure during this vulnerable period can induce persistent brain and behavioural alterations. The aim of this study was to compare the long-term cognitive consequences of chronic adolescence cannabinoid exposure between Lister Hooded rats and Wistar rats. Rats of both strains were injected daily throughout their adolescent or adult periods with vehicle or with incremental doses of the synthetic cannabinoid CB1 receptor agonist CP55,940 (CP). Short-term and spatial working memories were assessed using the object recognition and object location, tasks respectively. For both tasks, the effect of a 30- or 120-min delay between the learning and the testing phase was investigated. In the object recognition task, adolescent CP exposure impaired short-term memory after both delays in both strains. In contrast, in the object location task, adolescent CP exposure impaired spatial working memory in the Wistar rats after a 30-min delay, whereas the Lister Hooded rats exhibited a similar effect only after a 120-min delay. In these tests, no long-term deleterious effects were found following adult CP exposure in either strain. Our results confirm that adolescence is a critical period for the deleterious effects of cannabinoids on cognition and that these deleterious effects on spatial working memory are more strain-dependent than the effects observed on short-term memory.

H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine.Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine.Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.

The development of new treatment alternatives for schizophrenia has been prevented by the unknown etiology of the illness and the divergence of results in the field. However, consistent neuropathological findings are emerging from anatomical areas known to be at the core of schizophrenia. If these deficiencies are replicated in animal models then such anomalies could become the target for a new generation of drugs.To determine if the methylazoxymethanol acetate (MAM) model, the heterozygote reeler mouse (HRM) and NMDA-antagonists treated rats replicate neuropathological deficits encountered in patients with schizophrenia and to establish if such changes could lead the search for developing novel treatment alternatives.Databases including MEDLINE, Cochrane and Ovid were searched; search terms included neuropathology, schizophrenia and animal models.NMDA-antagonist treated animals partially replicate schizophrenia anomalies in parvalbumin positive interneurons. In contrast, neuroanatomical deficiencies replicated by the MAM model and the HRM in the hippocampus and the prefrontal cortex seem promising targets for future pharmacological research in schizophrenia. Such neuroanatomical findings along with evidence from molecules and genes associated with schizophrenia suggest new drugs should aim to correct deficits in the formation of dendrites and axons that seems to be implicated in this illness pathophysiology.

Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data.The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia.We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.).A significant attenuation of the MK-801-induced increase in glutamate levels associated with a potentiation of the increase in noradrenaline concentrations was found in the mPFC of MAM-exposed rats, whereas no significant change was observed in the NAcc. MAM-exposed rats also exhibited an exaggerated locomotor hyperactivity, in line with the exacerbation of symptoms reported in schizophrenic patients after administration of noncompetitive NMDA antagonists.Given the importance of the mPFC in regulating the hyperlocomotor effect of NMDA antagonists, our results suggest that the prefrontal neurochemical alterations induced by MK-801 may sustain the exaggerated locomotor response in MAM-exposed rats.

Engrailed1andEngrailed2 (En1andEn2) are two developmental genes of the homeogene family expressed in the developing midbrain.En1and, to a lesser degree,En2also are expressed in the adult substantia nigra (SN) and ventral tegmental area (VTA), two dopaminergic (DA) nuclei of the ventral midbrain. In an effort to studyEn1/2adult functions, we have analyzed the phenotype of mice lacking oneEn1allele in anEn2wild-type context. We show that in this mutant the number of DA neurons decreases slowly between 8 and 24 weeks after birth to reach a stable 38 and 23% reduction in the SN and VTA, respectively, and that neuronal loss can be antagonized by En2 recombinant protein infusions in the midbrain. These loss and gain of function experiments firmly establish thatEn1/2is a true survival factor for DA neuronsin vivo. Neuronal death in the mutant is paralleled by a 37% decrease in striatal DA, with no change in serotonin content. Using established protocols, we show that, compared with their wild-type littermates,En1+/− mice have impaired motor skills, an anhedonic-like behavior, and an enhanced resignation phenotype; they perform poorly in social interactions. However, these mice do not differ from their wild-type littermates in anxiety-measuring tests. Together, these results demonstrate thatEn1/2genes have important adult physiological functions. They also suggest that mice lacking only oneEn1allele could provide a novel model for the study of diseases associated with progressive DA cell death.

In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood.

Despite a delayed emergence of the symptoms, schizophrenia is thought to be a late consequence of early disturbances during development. Several reports have found decreased levels of reelin in the cortex and the hippocampus of postmortem brains of schizophrenic patients. In the rat, intraperitoneal injection of the anti-mitotic agent methylazoxymethanol (MAM) during intra-uterine development (embryonic day 17) induces cytoarchitectural abnormalities in the hippocampus and the cortex and behavioural changes reminiscent of positive, negative and cognitive symptoms of schizophrenia. We aimed to examine whether a transient prenatal disturbance of neurogenesis induces postnatal changes in the expression of reelin in the hippocampus. Cellular modifications were explored using hippocampal organotypic slice cultures, which allow for conservation of the in vivo cytoarchitecture. MAM effect on hippocampal neurogenesis was confirmed by birthdating experiments. After 3 weeks in vitro, reelin was expressed by calretinin-negative cells. The number of reelin-positive neurons was increased whereas the total neuron number was decreased in the stratum oriens in the E17 MAM-exposed animals as compared to the control group. Not only an increase in the number of cells expressing reelin was observed, but there was also a slight increase in reelin mRNA levels in hippocampal pyramidal cells of MAM-exposed animals. In contrast, there was no significant change in the dentate gyrus. These results show that transient prenatal disturbance of neurogenesis induces long-term modifications in specific areas of the hippocampus and in particular in the number of neurons expressing reelin. They also confirm the value of organotypic slices to study postnatal maturation in the hippocampus.

Schizophrenia is characterized by severe abnormalities in cognition, including disordered attention. In the rat, neonatal ventral hippocampal (NVH) lesions induce behavioral abnormalities at adulthood thought to simulate some aspects of the symptomatology of schizophrenia. Here, we compared the effects of NVH and adult ventral hippocampal (AVH) lesions on attentional performance as assessed by the five-choice serial reaction time task (5-CSRTT). NVH-lesioned rats were slower to acquire the task than AVH-lesioned and control animals. When training was complete, NVH- and AVH-lesioned animals exhibited stable but disrupted performance under standard conditions, thus emphasizing an implication of VH in visual attentional processes. Variations in task parameters induced a significantly greater disruption in NVH- and AVH-lesioned groups as compared to controls. NVH-lesioned rats were also hyper-responsive to the disruptive effects of a high dose of phencyclidine (PCP) (3 mg/kg). In contrast, amphetamine (0.4-0.8 mg/kg) had a similar effect in control and VH-lesioned rats. Thus, NVH-lesioned rats were impaired in the acquisition of stable performance in the 5-CSRTT, and were hypersensitive to the cognitive-impairing effects of PCP.

The abuse liability of Ro 64-6198, an orphanin FQ (OFQ) receptor full agonist that exhibits anxiolytic properties, was evaluated using an unbiased conditioned place preference (CPP) paradigm in rats. As OFQ is structurally related to opioid peptides and also exhibits anxiolytic-like properties, the effect of Ro 64-6198 on CPP was compared with those of morphine and alprazolam. We show here that neither Ro 64-6198 nor alprazolam exhibited rewarding or aversive properties, whereas morphine induced a pronounced CPP. These results strengthen the previous finding that Ro 64-6198 lacked abuse liability in a self-stimulation paradigm, suggesting that this new class of anxiolytic drugs is devoid of the risk for potential non-medical use and dependence.

This chapter provides an overview on exposure to methylazoxymethanol (MAM) at embryonic day 17 as a promising animal model for schizophrenia that mimics behavioral abnormalities and deficits in prefrontal cortex networks. This early insult produces in adult offspring from E17 MAM-treated dams the following: (1) behavioral changes including spontaneous hyperactivity and hypersensitivity to psychotomimetic drugs that are reminiscent of positive symptoms of schizophrenia and associated with a temporal pattern of expression; (2) impaired social interaction similar to that observed in schizophrenic patients existing prior to the onset of disease; (3) cognitive deficits in a variety of domain: working and reference memory, behavioral flexibility, attentional functioning, object recognition, and reversal learning; (4) behavioral abnormalities resembling schizophrenia-related endophenotypes like deficient sensorimotor gating and disrupted latent inhibition; (5) anatomical changes with cortical, thalamic, and hippocampal reductions in volume that are associated with an enlargement of the lateral ventricles; and (6) abnormalities in functional connectivity between brain areas that involve deficits in dopamine, glutamate, and GABA systems. The E17 MAM model that incorporates neuropathological and functional manifestations associated with schizophrenia may help forward early preventive interventions that can successfully reduce the risk of developing schizophrenia in exposed individuals.

Exposure to methylazoxymethanol (MAM) at embryonic day 17 (E17) in the rat has been proposed to be a promising model for schizophrenia that mimics behavioural abnormalities and deficits in prefrontal cortex (PFC) networks. In this study, we investigated for the first time the effects of antipsychotics on abnormal behaviours observed in prenatally MAM-exposed rats. We first examined spontaneous and MK-801-induced locomotor activity in an open field in adult E17 MAM- or saline-exposed rats. Then, the effect of single injections of haloperidol, clozapine and risperidone was investigated in MAM- or sham-exposed rats on spontaneous and MK-801 (0.05 mg/kg)-induced hyperactivity. Risperidone more selectively counteracted the spontaneous hyperactivity in MAM than in sham rats, while haloperidol and clozapine induced similar effects on spontaneous locomotion in both groups. The main result of this study is that all the tested antipsychotics were more effective in attenuating the MK-801-induced hyperlocomotion in MAM than in sham rats. These findings further support the validity of E17 MAM exposure as a model for schizophrenia and add to its heuristic value in screening therapies for schizophrenia.

BackgroundAdult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.Principal findingsCompared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.ConclusionsOur results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

The exposure to methylazoxymethanol (MAM) at embryonic day 17 (E17) results in behavioral anomalies in male rats that mimic several features of schizophrenia, including their emergence after puberty. Given that both men and women are likely to develop this illness and that currently no animal model is validated for females, we examined the behavioral consequences of E17 MAM exposure in female rats. We compared E17 MAM- and saline-exposed female rats before and/or after puberty for spontaneous activity, alternance and spatial recognition (Y-maze), spatial learning (Morris water maze), and sensory gating using the prepulse inhibition task. MAM-exposed female rats exhibited a significant increase in spontaneous locomotor activity in a novel environment, compared to sham animals, which emerged only after puberty. They also had deficits in spontaneous alternation performance and spatial recognition in a Y-maze as well as reference memory deficits in a Morris water maze task. Lastly, MAM-exposed female rats spent significantly less time in social interaction at both pre- and post-puberty and had a deficit in prepulse inhibition of the startle reflex (PPI) at adulthood. In conclusion, the present results show that, in female rat, exposure to MAM at E17 results in a pattern of behavioral changes that, on the whole, mimic positive, negative, and cognitive dimensions of schizophrenia. E17 MAM exposure thus appears to be a valid model for schizophrenia in both males and females.

Background Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N -methyl-d-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion–induced PPI deficits in rats. Methods Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. Results Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. Conclusions These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.

Rationale. Neonatal ventral hippocampal lesions in rats have been shown to result in behavioral abnormalities at adulthood thought to simulate some aspects of positive and cognitive deficits classically observed in schizophrenic patients. Objectives. We investigated whether such lesions can also induce deficits in reward sensitivity that are related to the negative symptoms of psychotic disorders. Methods. To investigate the effects of neonatal and adult lesions of the ventral hippocampus on reward-related behaviors we used the conditioned place preference (CPP) test and the saccharin consumption model. Results. In contrast to adult-lesioned animals, neonatally lesioned rats exhibited a deficit in amphetamine-induced CPP and a significant reduction in saccharin preference. These deficits are unlikely due to lesion-induced motor impairments as both neonatal- and adult-lesioned rats exhibited a similar hyperlocomotor response to amphetamine. Conclusions. Taken together, these results show that neonatal ventral hippocampal lesions induce a reduction in reward-seeking behaviors in adulthood that mimic some aspects of the negative symptoms (anhedonia) in psychotic patients.

Affecting 1% of worldwide population, schizophrenia is a debilitating pathology. Whether the aetiology of schizophrenia remains unknown, its multifactorial aspect is conversely now well admitted, and certainly gathers genetic vulnerability and environmental factors. Actual treatments are still unmet, particularly for negative and cognitive symptoms. For a better translation from treatments design of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models that considers the multifactorial aspects of this disease.We developed a new murine multifactorial model of schizophrenia (3-hit), that possesses a strong construct validity. To this, we combined a genetic predisposition (1st hit: partial deletion of MAP-6) with an early postnatal stress (2nd hit: 24 h maternal separation at postnatal day 9), and a late cannabinoid exposure during adolescence (3rd hit: tetrahydrocannabinol THC from post-natal day 32 to 52; 8 mg/kg/day).First, we characterised a promising face validity through behavioural, imaging and electrophysiological studies. At behavioural level, we demonstrated that 3-hit mice displayed negative-like symptoms, cognitive deficits and altered olfactory laterality. Moreover, we showed a sensory motor gating deficit, that is a major translational clue for animal models of schizophrenia. Additionally, 3-hit mice displayed some characteristic morphological and functional impairments of the disease: reduced hippocampal volume, altered callosal fibres, glutamatergic and GABAergic neurotransmission dysfunctions. We moreover highlighted some sexual dimorphisms.Second, we compared deficits of 3-hit mice to those of others models of schizophrenia developed in our laboratory. Deficits induced by one factor, or combination of several factors, evidenced a synergistic effect, and not a simple addition between each of them.The 3-hit model therefore presents strong construct validity and promising face validity, encouraging to assess the pharmacological validity., La schizophrénie est une maladie psychiatrique très invalidante qui concerne près de 1% de la population. Bien que son étiologie soit toujours inconnue, elle est certainement multifactorielle et comprend une interaction entre prédisposition génétique et facteurs environnementaux. Il existe des traitements médicamenteux mais ils ne sont pas totalement efficaces, particulièrement pour la prise en charge des symptômes négatifs et des déficits cognitifs. Le développement de nouveaux traitements plus efficaces passe par l’amélioration des modèles animaux prenant en compte le caractère multifactoriel de l’étiologie de cette pathologie.Nous avons développé un modèle murin multifactoriel de schizophrénie innovant (modèle 3-hit) présentant une forte validité de construction. Pour cela, nous avons combiné une modification génétique (1er hit : délétion partielle du gène MAP6) avec un stress environnemental précoce (2nd hit : séparation maternelle de 24h au 9ème jour de vie) et une exposition tardive au THC durant l’adolescence (3ème hit : administration quotidienne de tétrahydrocannabinol à 8mg/kg du 32ème au 52ème jour).Dans un premier temps, nous avons montré une bonne validité d’apparence de ce modèle à travers des études comportementale, en imagerie et en électrophysiologie. En effet, au niveau comportemental les souris 3-hit présentent des symptômes de type négatif, des déficits cognitifs et une altération de la latéralité olfactive. Nous avons aussi montré un déficit d’inhibition du réflexe de sursaut, qui est un élément comportemental clef dans les modèles animaux de schizophrénie, car il est également utilisé en recherche clinique. Nous avons également observé certaines altérations morphologiques et fonctionnelles cérébrales caractéristiques de la schizophrénie comme une réduction du volume de l’hippocampe, une altération des fibres du corps calleux et un dysfonctionnement des systèmes de neurotransmission glutamatergique et GABAergique. Certains dimorphismes sexuels ont été également montrés dans nos études.Dans un deuxième temps, nous avons comparé les déficits des animaux 3-hit avec ceux d’autres modèles de schizophrénie développés au laboratoire. La caractérisation des effets de chaque facteur, indépendamment et en association, nous a permis de mettre en évidence un phénomène de synergie entre les facteurs et non une simple addition des déficits induits par chacun d’entre eux.Le modèle de schizophrénie 3-hit présente de bonnes validités de construction et d’apparence, il est maintenant nécessaire afin de parfaire sa caractérisation de tester sa validité pharmacologique.