Search

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over-generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.

Cognitive, Affective and Behavioral Neuroscience, 15 (4), ISSN:1530-7026, ISSN:1531-135X

Rationale: Pre-exposure to either one of the two to-be-associated stimuli alone is known to reduce the efficiency of the learning of their association when they are subsequently paired explicitly. In classical conditioning, pre-exposure to the conditioned stimulus (CS) gives rise to latent inhibition (LI); and pre-exposure to the unconditioned stimulus (US) results in the US pre-exposure effect (USPEE). Considerable evidence supports an important role of central dopamine in the regulation and modulation of LI; it has been suggested that the USPEE may be similarly controlled by dopamine, but this parallelism has only been directly demonstrated in the conditioned taste aversion paradigm. Objective: The present study tested this hypothesis by comparing the efficacy of systemic amphetamine treatment to affect the expression of LI and the USPEE in a two-way active avoidance paradigm. Methods: C57BL/6 male mice were tested in active avoidance using a tone CS and a foot-shock US. Twenty-four hours before, they were pre-exposed to 100 presentations of the CS or the US, or to the test apparatus only. Amphetamine (2.5mg/kg) or saline was administered before stimulus pre-exposure and conditioned avoidance test, in which the mice learned to avoid the shock by shuttling in response to the tone. Results: Amphetamine disrupted both stimulus pre-exposure effects, thus, lending further support to the hypothesis that the USPEE is similar to LI in its sensitivity to dopamine receptor agonist. Hence, the USPEE paradigm may represent a valuable addition to the study of dopamine-sensitive processes of selective learning currently implicated in LI and Kamin blocking

Psychopharmacology, 179 (1), ISSN:0033-3158, ISSN:1432-2072

The water maze is one of the most widely employed spatial learning paradigms in the cognitive profiling of genetically modified mice. Oftentimes, tests of reference memory (RM) and working memory (WM) in the water maze are sequentially evaluated in the same animals. However, critical difference in the rules governing efficient escape from the water between WM and RM tests is expected to promote the adoption of incompatible mnemonic or navigational strategies. Hence, performance in a given test is likely poorer if it follows the other test instead of being conducted first. Yet, the presence of such negative transfer effects (or proactive interference) between WM and RM training in the water maze is often overlooked in the literature. To gauge whether this constitutes a serious concern, the present study determined empirically the magnitude, persistence, and directionality of the transfer effect in wild-type C57BL/6 mice. We contrasted the order of tests between two cohorts of mice. Performance between the two cohorts in the WM and RM tests were then separately compared. We showed that prior training of either test significantly reduced performance in the subsequent one. The statistical effect sizes in both directions were moderate to large. Although extended training could overcome the deficit, it could re-emerge later albeit in a more transient fashion. Whenever RM and WM water maze tests are conducted sequentially in the same animals – regardless of the test order, extra caution is necessary when interpreting the outcomes in the second test. Counterbalancing test orders between animals is recommended. Fil: Serrano Sponton, Lucas Ezequiel. Mainz University Hospital. Department of Neurosurger; Alemania. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina Fil: Soria, Gonzalo Jose. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina Fil: Dubroqua, Sylvain. Institute of Brain and Cognitive Science; China. Laboratory of Behavioural Neurobiology; Suiza Fil: Singer, Philipp. Institute of Brain and Cognitive Science; China. Roche Diagnostics; Suiza Fil: Feldon, Joram. Laboratory of Behavioural Neurobiology; Suiza. Roche Diagnostics; Suiza Fil: Gargiulo, Pascual Angel. Universidad Nacional de cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina Fil: Yee, Benjamin K.. Laboratory of Behavioural Neurobiology; Suiza. The Hong Kong Polytechnic University. Faculty of Health and Social Sciences,; China

Restricted structural re-growth in the adult CNS is a major limitation to fully functional recovery following extensive CNS trauma. This limitation is partly due to the presence of growth inhibitory proteins, in particular, Nogo-A. Pre-clinical studies have demonstrated that intrathecally infused anti-Nogo-A antibodies are readily distributed via the cerebrospinal fluid penetrating throughout the spinal cord and brain, where they promote sprouting, axonal regeneration and improved functional recovery after CNS injury. Whether anti-Nogo-A treatments of intact animals might induce behavioral alterations has not been systematically tested. This is addressed here in an adult rat model of chronic intrathecal infusion of function-blocking anti-Nogo-A antibodies for 2 to 4weeks. We observed by proteomic and immunohistochemical techniques that chronic Nogo-A neutralization in the intact CNS increased expression of cytoskeletal, fiber-growth-related, and synaptic proteins in the hippocampus, a brain region which might be particularly sensitive to Nogo-A depletion due to the high expression level of Nogo-A. Despite such molecular and proteomic changes, Nogo-A blockade was not associated with any pronounced cognitive-behavioral changes indicative of hippocampal functional deficiency across several critical tests. Our results suggest that the plastic changes induced by Nogo-A blockade in the adult hippocampus are counter-balanced by homeostatic mechanisms in the intact and the injured CNS. The data indicate that anti-Nogo-A therapy appears safe in the adult CNS over 4weeks of continuous administration.

Overshadowing (Experiment 1) and blocking (Experiment 2) were investigated using a conditioned suppression paradigm in rats. Neither hippocampectomy nor cortical control lesions affected the extent to which a salient stimulus overshadowed a less salient one. Nor did the lesions affect the extent to which a stimulus that was highly correlated with shock overshadow a stimulus that was less well correlated with shock. Finally, the lesions did not alter the extent to which a previously reinforced stimulus blocked conditioning to another stimulus when both were presented as a reinforced compound stimulus. It is thus possible for hippocampectomized rats to show apparently normal overshadowing and blocking, at least under some testing conditions.

Experiment I assessed the effect of cytotoxic retrohippocampal (entorhinal and extra-subicular cortices) lesions on the development of latent inhibition (LI) using an off-the-baseline, between-subjects, conditioned emotional response paradigm. Sham-operated controls and unoperated rats that had been pre-exposed to a light stimulus prior to light-shock pairings showed less conditioned suppression towards the light stimulus than the nonpre-exposed animals, thus demonstrating LI. However, LI was not evident in rats with retrohippocampal lesions. In experiment 2, the same animals were trained to run in an straight runway for food. Half of the animals were trained under a 50% partial reinforcement schedule (i.e. they were rewarded randomly on half of the acquisition trials) and the other half were trained under a continuous reinforcement schedule (i.e. they were rewarded on every acquisition trial). When tested in extinction, animals trained on the partial reinforcement schedule showed greater persistence than animals trained on continuous reinforcement, thus demonstrating the partial reinforcement extinction effect (PREE). Rats with retrohippocampal lesions showed a PREE that was at least as clear as that seen in the sham-operated controls and in the unoperated animals. It is concluded that cytotoxic lesions of the retrohippocampal region selectively led to an abolition of LI, but spared the PREE. The present study thus provided evidence against the hypothesis that LI and the PREE share a common neural substrate.

Pharmacotherapy of schizophrenia based on the dopamine hypothesis remains unsatisfactory for the negative and cognitive symptoms of the disease. Enhancing N-methyl-D-aspartate receptors (NMDAR) function is expected to alleviate such persistent symptoms, but successful development of novel clinically effective compounds remains challenging. Adenosine is a homeostatic bioenergetic network modulator that is able to affect complex networks synergistically at different levels (receptor-dependent pathways, biochemistry, bioenergetics, and epigenetics). By affecting brain dopamine and glutamate activities, it represents a promising candidate for reversing the functional imbalance in these neurotransmitter systems believed to underlie the genesis of schizophrenia symptoms, as well as restoring homeostasis of bioenergetics. Suggestion of an adenosine hypothesis of schizophrenia further posits that adenosinergic dysfunction might contribute to the emergence of multiple neurotransmitter dysfunctions characteristic of schizophrenia via diverse mechanisms. Given the importance of adenosine in early brain development and regulation of brain immune response, it also bears direct relevance to the aetiology of schizophrenia. Here, we provide an overview of the rationale and evidence in support of the therapeutic potential of multiple adenosinergic targets, including the high-affinity adenosine receptors (A(1)R and A(2A)R), and the regulatory enzyme adenosine kinase (ADK). Key preliminary clinical data and preclinical findings are reviewed.

Prenatal exposure to infection has been linked to increased risk of neurodevelopmental brain disorders, and recent evidence implicates altered dopaminergic development in this association. However, since the relative risk size of prenatal infection appears relatively small with respect to long-term neuropsychiatric outcomes, it is likely that this prenatal insult interacts with other factors in shaping the risk of postnatal brain dysfunctions. In the present study, we show that the neuropathological consequences of prenatal viral-like immune activation are exacerbated in offspring with genetic predisposition to dopaminergic abnormalities induced by mutations inNurr1, a transcription factor highly essential for normal dopaminergic development. We combined a mouse model of heterozygous genetic deletion ofNurr1with a model of prenatal immune challenge by the viral mimetic poly(I:C) (polyriboinosinic polyribocytidilic acid). In our gene–environment interaction model, we demonstrate that the combination of the genetic and environmental factors not only exerts additive effects on locomotor hyperactivity and sensorimotor gating deficits, but further produces synergistic effects in the development of impaired attentional shifting and sustained attention. We further demonstrate that the combination of the two factors is necessary to trigger maldevelopment of prefrontal cortical and ventral striatal dopamine systems. Our findings provide evidence for specific gene–environment interactions in the emergence of enduring attentional impairments and neuronal abnormalities pertinent to dopamine-associated brain disorders such as schizophrenia and attention deficit/hyperactivity disorder, and further emphasize a critical role of abnormal dopaminergic development in these etiopathological processes.

Neural Plasticity, 2017, ISSN:2090-5904, ISSN:1687-5443

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the development and maintenance of dopaminergic neurons. Reduced expression of Nurr1 has been linked to the etiopathogenesis of Parkinson's disease and other dopamine-related disorders such as schizophrenia. Recent experimental work in mice with a heterozygous constitutive deletion of Nurr1 has revealed that this genetic manipulation leads to the presence of sensorimotor gating dysfunctions in the form of reduced prepulse inhibition of the acoustic startle reflex. However, the neuronal substances for this behavioral manifestation remain essentially unknown. Since converging evidence supports a key role of the central dopamine system in the regulation of prepulse inhibition, we hypothesized that the emergence of prepulse inhibition deficits in adult Nurr1-deficient mice may be linked to dopaminergic neuroanatomical changes. To test this hypothesis, we followed a within-subject approach in which sensorimotor gating performance was correlated with post-mortem expression of several dopaminergic markers in relevant striatal and midbrain regions. We found that prepulse inhibition deficits in Nurr1-deficient mice were paralleled by reduced numbers of substantia nigra dopamine cells expressing tyrosine hydroxylase, and by decreased tyrosine hydroxylase and dopamine transporter immunoreactivity in ventral parts of the striatum. Most interestingly, we also revealed a striking negative correlation between prepulse inhibition levels and tyrosine hydroxylase immunoreactivity in Nurr1-deficient mice in dorsal striatal regions (caudate putamen) and ventral striatal regions (nucleus accumbens core and shell). Our findings thus suggest that the emergence of prepulse inhibition deficits induced by heterozygous constitutive deletion of Nurr1 is, at least in part, related to alterations in presynaptic components of the striatal dopamine system. The constellation of neuroanatomical and behavioral alterations in Nurr1-deficient mice observed here confirms previous impressions that the consequences of Nurr1 down-regulation capture neuronal and behavioral pathologies relevant especially for (but not limited to) Parkinson's disease.

The adenosine A2A receptor (A2AR) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A2AR inactivation can be pro-cognitive, analyses of A2AR's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A2ARs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A2ARs. Specifically, we evaluated the cognitive impacts of conditional A2AR deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A2AR KO) or to striatum alone (st-A2AR KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A2AR-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility—enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A2ARs as they were captured by A2AR deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D1, D2, or A1 receptor expression was found. This study provides the first direct demonstration that targeting striatal A2ARs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1-deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder.

Prenatal exposure to infection and subsequent inflammatory responses have been implicated in the etiology of schizophrenia and autism. In this review, we summarize current evidence from human and animal studies supporting the hypothesis that the pathogenesis of these two disorders is linked via exposure to inflammation at early stages of development. Moreover, we propose a hypothetical model in which inflammatory mechanisms may account for multiple shared and disorder-specific pathological characteristics of both entities. In essence, our model suggests that acute neuroinflammation during early fetal development may be relevant for the induction of psychopathological and neuropathological features shared by schizophrenia and autism, whereas postacute latent and persistent inflammation may contribute to schizophrenia- and autism-specific phenotypes, respectively.

Often factors related to hippocampal neurogenesis also result in a myriad of confounding changes that might explain or mediate the concomitant effects in memory and learning performance. Dr. Lazic's article (2010) reiterates such concerns in interpreting the biological links between neurogenesis and learning in the context of aging as articulated previously by Baxter and Gallagher (2006). The correlative analysis published by Nyffeler et al. (2008) illustrates the problematic inherent to such an interpretation. We offer here a complimentary approach that is both intuitive and practical in the re-examination of the previously reported data set, which further supports Nyffeler et al.'s (2008) key findings and conclusion.

Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder.

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, but they also offer important new avenues for the elucidation of neurobiological, neuroendocrine and neuroimmunological mechanisms involved in the etiopathogenesis of schizophrenia and related disorders.

The brain-specific Ras ⁄Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK ⁄MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG + ⁄ ) ), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG + ⁄ ) mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG + ⁄ ) mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition memory performance was not impaired in SG + ⁄ ) mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG + ⁄ ) mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation.

Introduction: The nature of deficits in tests of sustained attention, planning and attentional set-shifting has not been investigated in neuroleptic-naïve first-episode (FE) schizophrenia patients. Based on previous literature of chronic and medicated FE schizophrenia patients, we predicted that the neuroleptic-naïve patients would show deficits in these cognitive processes. Methods: Twenty-nine neuroleptic-naïve FE schizophrenia patients and 33 healthy controls – matched by age, gender, and nicotine consumption – performed 3 tests from the Cambridge Automated Neuropsychological Test Battery (CANTAB) thought to measure these cognitive processes: the Rapid Visual Information Processing task (RVIP, sustained attention), the Stockings of Cambridge task (SOC, planning), and the Intradimensional/Extradimensional set-shifting task (IDED, attention shifting). Results: The patients were significantly impaired in the sensitivity index (A′) of the RVIP, and in the number of problems solved with minimum moves on the SOC. Nevertheless, the groups did not differ regarding the number of participants who failed at the crucial extradimensional shift stage of the IDED. Conclusion: Sustained attention and planning abilities are already impaired in neuroleptic-naïve FE schizophrenia patients, whereas set-shifting abilities as measured with the IDED task seem to be intact at illness onset. Since chronic schizophrenia patients have been shown to have impaired IDED performance, we tentatively propose that IDED performance deteriorates over time with illness chronicity and/or medication.

Maternal infection during pregnancy is a notable risk factor for the offspring to develop severe neuropsychiatric disorders, including schizophrenia. One prevalent hypothesis suggests that infection-induced disruption of early prenatal brain development predisposes the organism for long-lasting structural and functional brain abnormalities, leading to the emergence of psychopathological behaviour in adulthood. The feasibility of this causal link has received considerable support from several experimental models established in both rats and mice. In this review, we provide an integrative summary of the long-term neuropathological consequences of prenatal exposure to infection and/or inflammation as identified in various experimental models of prenatal immune challenge. In addition, we highlight how abnormalities in distinct brain areas and neurotransmitter systems following prenatal immune activation may provide a neural basis for the emergence of specific forms of psychosis-related behaviour. Specifically, we suggest that prenatal infection-induced imbalances in the mesolimibic and mesocortical dopamine pathways may constitute critical neural mechanisms for disturbances in sensorimotor gating, abnormalities in selective associative learning and hypersensitivity to psychostimulant drugs. On the other hand, the emergence of working memory deficiency following prenatal immune challenge may be crucially linked to the concomitant disruption of GABAergic and glutamatergic functions in prefrontal cortical and hippocampal structures. Notably, many of the identified neuronal abnormalities are directly implicated in the neuropathology of schizophrenia. The findings from prenatal infection models of schizophrenia thus provide considerable experimental evidence for the assumption that prenatal exposure to infection and/or inflammation is a relevant environmental link to specific neuronal abnormalities underlying psychosis-related behaviour in humans.

Prepulse inhibition (PPI) of the acoustic startle reflex has been extensively employed as a test of sensorimotor gating or early attentional control in neuropsychiatric research, because a number of psychiatric conditions, including schizophrenia, exhibit PPI deficiencies. In both human and animal studies, PPI is commonly demonstrated by an attenuation of the acoustic startle reflex when the startle-inducing pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This weakening of the startle reaction is attributed to, and therefore also provides an indirect measure of, the inhibition triggered by the perception of the prepulse stimulus. The relative ease in measuring the overt pulse-elicited startle reaction, in comparison with the relatively weak prepulse-elicited reaction (PPER) has led to a near complete neglect of the latter in recent literature. However, the assumption that the prepulse used in PPI is non-startling, does not imply that it is associated with no measurable responses. In fact the feasibility and reliability of obtaining such measures has been confirmed in both rodents and humans, and here we review the key findings derived from the direct evaluation of prepulse-elicited reaction in PPI, including under conditions that lead to PPI deficits. The theoretical implications and potential interpretative values of PPER are discussed. It is concluded that PPER should no longer be ignored; its emphasis may shed light on the kind of inhibition or gating dysfunction relevant to PPI disruption seen in pathological conditions including schizophrenia.

Prenatal stress can affect foetal neurodevelopment and result in increased risk of depression in adulthood. It promotes increased maternal hypothalamo-pituitary-adrenal gland (HPA) secretion of glucocorticoid (GC), leading to increased foetal and maternal GC receptor activity. Prenatal GC receptor activity is also increased during prenatal treatment with dexamethasone (DEX), which is commonly prescribed as a prophylactic treatment of preterm delivery associated morbid symptoms. Here, we exposed pregnant Wistar rats to 0.1 mg/kg/d DEX during the last week of pregnancy and performed cross-fostering at birth. In the adult offspring we then studied the effects of prenatal DEX exposure per se and the effects of rearing by a dam exposed to prenatal DEX. Offspring were assessed in the following paradigms testing biobehavioural processes that are altered in depression: progressive ratio schedule of reinforcement (anhedonia), Porsolt forced swim test (behavioural despair), US pre-exposure active avoidance (learned helplessness), Morris water maze (spatial memory) and HPA axis activity (altered HPA function). Responsiveness to a physical stressor in terms of HPA activity was increased in male offspring exposed prenatally to DEX. Despite this increased HPA axis reactivity, we observed no alteration of the assessed behaviours in offspring exposed prenatally to DEX. We observed impairment in spatial memory in offspring reared by DEX exposed dams, independently of prenatal treatment. This study does not support the hypothesis that prenatal DEX exposure leads to depression-like symptoms in rats, despite the observed sex-specific programming effect on HPA axis. It does however emphasise the importance of rearing environment on adult cognitive performances.

The specific glycine transporter 1 (GlyT1) inhibitor, SSR504734, is highly effective in enhancing N-methyl-D-aspartate receptor (NMDAR) function by elevating the availability of the NMDAR co-agonist, glycine, in the vicinity of NMDAR-containing glutamatergic synapses. According to the glutamatergic hypofunction hypothesis of schizophrenia, SSR504734 may therefore possess antipsychotic potential. Here, we evaluated the effects of SSR504734 in response to three psychomimetic drugs: phencyclidine, amphetamine, and apomorphine in male C57BL/6 mice. SSR504734 attenuated phencyclidine-induced (5 mg/kg, i.p.) hyperlocomotion, but potentiated the motor stimulant and motor depressant effects of amphetamine (2.5 mg/kg, i.p.) and apomorphine (0.75 mg/kg, s.c.), respectively. Hence, SSR504734 not only confers resistance to NMDAR blockade, but also enhances the locomotor response to dopaminergic stimulation. The latter finding adds to reports that SSR504734 may modulate dopamine-mediated behaviour by interference with normal glutamate-dopamine interaction. The specificity of this action of SSR504734 will be highly relevant to its potential application as an antipsychotic agent.

Psychopharmacology, 206 (4), ISSN:0033-3158, ISSN:1432-2072

Objectives Latent inhibition (LI) refers to the retarding effects of inconsequential stimulus preexposure on subsequent conditioning to that stimulus, and reflects the organism’s capacity to ignore irrelevant stimuli. LI is disrupted in schizophrenia patients, due to faster learning of the association between the conditioned stimulus (CS) and an unconditioned stimulus (US). It was recently proposed that LI has an additional pole of abnormality indicated by LI persistence. Methods Two experiments were performed to test this hypothesis. Both experiments applied a new within-subject, visual recognition LI procedure in which the association between a cue (CS) and the target (US) is acquired. In Exp 1 the task was applied to healthy volunteers (n = 21). In Exp 2 chronic schizophrenia patients (n = 19) were compared to control subjects (n = 20). Results In Exp 1 the subjects showed LI in the initial trials of cue–target pairings, and an attenuation of the phenomenon at later trials. In Exp 2 control subjects showed a pattern of response comparable to the subjects of Exp 1, while the patients showed LI only on the later trials of the task. Conclusions This result suggests that patients with chronic schizophrenia showed LI persistence. The possible advantages of the new LI paradigm are discussed.

Deficient sensorimotor gating as indexed by prepulse inhibition (PPI) of the startle response has been reported repeatedly in patients suffering from schizophrenia. According to the widely accepted “protective hypothesis,” PPI reflects the protection of ongoing information processing against interference by other stimuli. Alternatively, it has been proposed that PPI might be regulated by startle reflex circuit excitability. In the present study, we evaluated these 2 conceptually divergent approaches underlying the regulation of PPI. To this end, we assessed sensorimotor gating as indexed by PPI, the reactivity to the prepulse-alone stimulus indexed as prepulse-elicited reactivity (PPER), and acoustic blink reflex excitability in terms of paired pulse suppression (PPS) within a single recording session in 13 unmedicated and 24 medicated (11 first break) schizophrenia patients in comparison to 43 healthy control subjects. The results showed that PPI was significantly reduced in unmedicated, but not in medicated schizophrenia patients. Furthermore, unmedicated patients could be distinguished from the medicated patients and control subjects in terms of PPER. In contrast to PPI, PPS did not differ between patients and control subjects. These findings are in line with the “protective hypothesis” of PPI and indicate that reduced sensorimotor gating in schizophrenia patients might be based on a reduced perception and/or processing of the prepulse stimulus. The extent to which PPER may or may not be causally associated with sensorimotor gating in schizophrenia has to be further investigated in human and animal studies.

The synaptic Ras/Rap-GTPase-activating protein (SynGAP) regulates specific intracellular events following N-methyl-d-aspartate receptor (NMDAR) activation. Here, the impact of SynGAP heterozygous knockout (SG +/― ) on NMDAR-dependent functions was assessed using different positive reinforcement schedules in instrumental conditioning. The knockout did not affect the temporal control of operant responding under a fixed interval (FI) schedule, but led to a putative enhancement in response vigor and/or disinhibition. When examined on differential reinforcement of low rates of response (DRL) schedules, SG +/― mice showed increased responding under DRL-4s and DRL-8s, without impairing the response efficiency (total rewards/total lever presses) because both rewarded and nonrewarded presses were elevated. Motivation was unaffected as evaluated using a progressive ratio (PR) schedule. Yet, SG +/― mice persisted in responding during extinction at the end of PR training, although an equivalent phenotype was not evident in extinction learning following FI-20s training. This extinction phenotype is therefore schedule-specific and cannot be generalized to Pavlovian conditioning. In conclusion, constitutive SynGAP reduction increases vigor in the execution of learned operant behavior without compromising its temporal control, yielding effects readily distinguishable from NMDAR blockade.

Gene-environment interactions are known to play a major role in the ethiopathology of several neuropsychiatric disorders, including Alzheimer's disease (AD). The present study investigates whether environmental manipulations, that is, social isolation, may affect the genetic predisposition to develop AD-related traits in a triple transgenic mouse model (3 x Tg-AD), as suggested by our previous study employing physical exercise (Pietropaolo et al., 2008). Mutant and wild type mice of both sexes were housed singly or in groups from weaning, and evaluated behaviorally at 6 to 7 months of age. Independent of sex, the 3 x Tg-AD genotype was associated with enhanced acoustic startle response, improved performance in the cued version of the water maze and a clear impairment in the Y maze. Notably, the female (but not male) mutant mice showed increased anxiety. Although social isolation was effective in modifying several behaviors, it did not exacerbate any of the AD-like symptoms. Our findings demonstrated the differential susceptibility of the 3 x Tg-AD mouse line to environmental manipulations, showing that social isolation did not induce remarkable effects on the genetically determined AD-like symptoms, in contrast to what previously observed with physical exercise.

The membrane protein Nogo-A inhibits neurite outgrowth and regeneration in the injured central nervous system, primarily because of its expression in oligodendrocytes. Hence, deletion of Nogo-A enhances regeneration following spinal cord injury. Yet, the effects of Nogo-A deletion on general behavior and cognition have not been explored. The possibility of potential novel functions of Nogo-A beyond growth inhibition is strongly suggested by the presence of subpopulations of neurons also expressing Nogo-A - not only during development but also in adulthood. We evaluated here Nogo-A(-/-) mice in a series of general basic behavioral assays as well as functional analyses related to brain regions with notable expression levels of Nogo-A. The SHIRPA protocol did not show any major basic behavioral changes in Nogo-A(-/-) mice. Anxiety-related behavior, pain sensitivity, startle reactivity, spatial learning, and associative learning also appeared indistinguishable between Nogo-A(-/-) and control Nogo-A(+/+) mice. However, motor co-ordination and balance were enhanced in Nogo-A(-/-) mice. Spontaneous locomotor activity was also elevated in Nogo-A(-/-) mice, but this was specifically observed in the dark (active) phase of the circadian cycle. Enhanced locomotor reaction to systemic amphetamine in Nogo-A(-/-) mice further pointed to an altered dopaminergic tone in these mice. The present study is the first behavioral characterization of mice lacking Nogo-A and provides significant insights into the potential behavioral relevance of Nogo-A in the modulation of dopaminergic and motor functions.

One of the key features of schizophrenia is the inability to filter out irrelevant stimuli which consequently leads to stimulus overload. There are different methods which aim at investigating these deficient filter mechanisms; one of these is the learned irrelevance (LIrr) paradigm. LIrr refers to the retardation of associative learning that occurs if the conditioned stimulus (CS) and the unconditioned stimulus (US) are preexposed in an explicitly unpaired manner prior to the establishment of the association between the stimuli. In the present study we used a recently developed computerized within-subject visual LIrr test. We measured 11 drug-naive first-episode schizophrenia patients and compared their performance to that of 17 healthy control subjects. LIrr was observed to be intact in normal individuals but disrupted in drug-naive first-episode schizophrenia patients. After one month elapsed, 5 of the 11 patients and 16 of the 17 control subjects were retested in a follow-up study. By this time, patients had been medicated with antipsychotic drugs for at least 3 weeks. While healthy controls exhibited a robust LIrr effect, patients still failed to show LIrr. Correlations were found between the performance of unmedicated patients and the depression component of the PANSS psychopathology scale.

There is growing interest in the effects of voluntary wheel running activity on brain and behaviour in laboratory rodents and their implications to humans. Here, the major findings to date on the impact of exercise on mental health and diseases as well as the possible underlying neurobiological mechanisms are summarised. Several critical modulating factors on the neurobehavioural effects of wheel running exercise are emphasized and discussed--including the amount of wheel running, sex and strain/species differences. We also reported the outcome of an empirical investigation of the impact of wheel running exercise on the expression of both cognitive and non-cognitive phenotypes in a triple (3 x Tg-AD) transgenic mouse model for Alzheimer's disease (AD). Clear sex- and paradigm-specific effects of exercise on the genetically determined phenotypes are illustrated, including the efficacy of wheel running activity in attenuating the sex-specific cognitive deficits. It is concluded that the wheel running paradigm represents a unique environmental manipulation for the investigation of neurobehavioural plasticity in terms of gene-environment interactions relevant to the pathogenesis and therapies of certain neuropsychiatric conditions.

Adaptive purposeful behaviour depends on appropriate modifications of synaptic connectivity that incorporate an organism's past experience. At least some forms of such synaptic plasticity are believed to be mediated by NMDA receptors (NMDARs). Complementary interaction with inhibitory neurotransmission mediated by GABA(A) receptors, and upstream control of the excitability of NMDARs by glycine availability can greatly influence the efficacy of NMDAR mediated neuroplasticity, and thereby exert significant effects on cognition. Memory, selective attention or sensorimotor gating functions can be modified in mice with a reduction of alpha(5)GABA(A) receptors in the hippocampus or a selective deletion of glycine transporter 1 (GlyT1) in the forebrain. Both genetic manipulations altered the formation or persistence of associative links leading to distinct phenotypes on trace conditioning, extinction learning, latent inhibition, working memory, and object recognition. Behavioural assays of latent inhibition, prepulse inhibition, working memory, and sensitivity to psychostimulants in particular suggest that alpha(3) and alpha(5) subunit-containing GABA(A) receptors as well as GlyT1 are potential sites for ameliorating psychotic-like behaviour. Taken together, these results qualify distinct GABA-A receptor subtypes and GlyT1 as molecular targets for the development of a new pharmacology in the treatment of cognitive decline and psychotic symptoms.

Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia and autism. However, only little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of brain and behavioral dysfunctions in later life. Using a mouse model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C), we explored the acute effects of maternal immune activation during pregnancy on the development of the fetal dopaminergic system, a neurotransmitter system known to be affected in schizophrenia and related disorders. We found that maternal immunological stimulation in early/middle pregnancy increased the number of mesencephalic dopamine neurons in the fetal brain at middle/late and late gestation. This effect was paralleled by changes in fetal expression of several genes known to be involved in dopamine neuron development, including the inductive signals sonic hedgehog (Shh) and fibroblast growth factor 8 (Fgf8), as well as transcription factors Nurr1 and Pitx3. These findings provide initial in vivo evidence for a modulation of fetal dopaminergic development by maternal immune activation during pregnancy. Additional investigations of the neurodevelopmental effects of prenatal immune challenge are thus clearly warranted in order to further validate whether abnormal dopaminergic development may be a critical neuropathological mechanism underlying the precipitation of schizophrenia-like brain and behavioral dysfunctions emerging after in utero exposure to infection.

Maternal infection during pregnancy increases the risk of schizophrenia and other brain disorders of neurodevelopmental origin in the offspring. A multitude of infectious agents seem to be involved in this association. Therefore, it has been proposed that factors common to the immune response to a wide variety of bacterial and viral pathogens may be the critical link between prenatal infection and postnatal brain and behavioral pathology. More specifically, it has been suggested that the maternal induction of pro-inflammatory cytokines may mediate the neurodevelopmental effects of maternal infections. Here, we review recent findings from in vitro and in vivo investigations supporting this hypothesis and further emphasize the influence of enhanced anti-inflammatory cytokine signaling on early brain development. Disruption of the fetal brain balance between pro- and anti-inflammatory cytokine signaling may thus represent a key mechanism involved in the precipitation of schizophrenia-related pathology following prenatal maternal infection and innate immune imbalances.

In rodents, social isolation during the early postweaning phase induces several behavioral abnormalities, commonly referred to as the isolation syndrome. We attempted to identify the contribution of the selective deprivation of physical contact to the emergence of the isolation syndrome. To this end, we devised a pseudoisolated housing condition in which male 3-week-old C57BL/6 mice were caged in pairs, but were separated by a transparent perforated partition allowing only nonphysical contact, and compared it with the classical isolation procedure and standard laboratory group housing. Locomotor activity, acoustic startle reactivity, and amphetamine-induced hyperactivity were enhanced by isolation, but neither anxiety nor prepulse inhibition of the acoustic startle response was affected. Pseudoisolated mice were comparable to grouped controls in their acoustic startle response and locomotor reactivity to amphetamine, but they were as active as isolated animals in the predrug sessions of the open field. Furthermore, pseudoisolation also exerted its own unique effects, namely, anxiolysis. Our results demonstrated for the first time the relevance of nonphysical contact including its ability to undermine the emergence of the isolation syndrome in mice.

The high-affinity glycine transporter 1 (GlyT1) is the primary endogenous regulator of glycine levels in the vicinity of the N-methyl-D-aspartate receptor (NMDAR). As a co-agonist, glycine can allosterically modulate NMDAR functions through its binding to the glycine binding site (glycine-B site). Under homeostatic conditions, GlyT1 mediated re-uptake is believed to maintain the synaptic glycine concentration below the saturation level of the glycine-B site. Given that glycine-B site occupation is obligatory for glutamatergic activation of the NMDAR, increased availability of glycine in the vicinity of NMDARs glycine-B site has been suggested as an alternate strategy to enhance NMDAR functions. Because exogenously administered glycine shows poor blood-brain barrier penetration and must overcome potent regulatory brain mechanisms in order to efficiently enhance NMDAR function, one currently favored strategy is to target the glycine clearance mechanism through inhibition of GlyT1 mediated re-uptake. Numerous studies have demonstrated that pharmacological blockade or molecular down-regulation of GlyT1 leads to enhanced NMDAR functions and thus may provide novel therapeutic avenues in the treatment of neurological and psychiatric disorders in which NDMAR hypofunction has been implicated, including schizophrenia. Several modulatory agents targeted at the glycine-B site are currently undergoing pre-clinical and clinical development as potential antipsychotic drugs. Parallel research in animals with pharmacological inhibition of GlyT1 or GlyT1 knock-out mice has also generated promising results, reinforcing the hypothesis that disruption of glycine reuptake via GlyT1 may entail therapeutic value against primarily negative and cognitive symptoms of schizophrenia.

The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an ‘upstream regulator’ of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-tg), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-tg mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-tg mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy.

Experimental animal studies and epidemiological and clinical human studies demonstrate that atypical infant-caregiving can exert short- and long-term effects on offspring phenotype, including increased long-term risk of affective disorders. Whilst the early environment is therefore a major determinant of behavioral, physiological and neurobiological phenotypes, the effects of early adversity exhibit individual variation, presumably due to differences in environment-genotype interactions. Twin studies provide a powerful model with which to study such interactions. However, human twin studies rarely include analysis of genotype-environment interactions or of individuals exposed to extreme environments, and rat studies have rarely attempted to utilize littermates (i.e. dizygotic twins) to investigate environment-genotype interactions. Here, we report on the effects of repeated deprivation of caregiving in the common marmoset, a primate that exhibits dizygotic twinning and bi-parental care. Breeding pairs each contributed early deprived (ED) twins and control (CON) twins, thereby allowing for the study of effects of ED, parentage and ED-parentage interaction. Significant ED x parentage interaction effects were obtained for basal urinary, plasma and cerebrospinal-fluid cortisol titers (infancy-adolescence), and basal levels of social and maintenance behaviors (juveniles); basal urinary cortisol titers during a 2-week period of repeated psychosocial challenge (juveniles), and social and exploratory behavior during psychosocial challenge (juveniles). Significant main effects of ED were obtained for: basal levels of time spent in contact with parents (EDCON; juveniles) and in locomotor activity (EDCON; adolescents); basal and psychosocial-stress-related systolic blood pressure (EDCON; juveniles); time spent in locomotor activity (EDCON), contact calling (EDCON) and exploring novelty (EDCON) during psychosocial challenge (juveniles). This study provides evidence for long-term effects of early environment on bio-behavioral traits and states in marmosets specifically, and the importance of including parental factors in developmental studies in mammals generally.

Neurotransmitter receptor density is a major variable in regulating synaptic strength. Receptors rapidly exchange between synapses and intracellular storage pools through endocytic recycling. In addition, lateral diffusion and confinement exchanges surface membrane receptors between synaptic and extrasynaptic sites. However, the signals that regulate this transition are currently unknown. GABAA receptors containing α5-subunits (GABAAR-α5) concentrate extrasynaptically through radixin (Rdx)-mediated anchorage at the actin cytoskeleton. Here we report a novel mechanism that regulates adjustable plasma membrane receptor pools in the control of synaptic receptor density. RhoA/ROCK signalling regulates an activity-dependent Rdx phosphorylation switch that uncouples GABAAR-α5 from its extrasynaptic anchor, thereby enriching synaptic receptor numbers. Thus, the unphosphorylated form of Rdx alters mIPSCs. Rdx gene knockout impairs reversal learning and short-term memory, and Rdx phosphorylation in wild-type mice exhibits experience-dependent changes when exposed to novel environments. Our data suggest an additional mode of synaptic plasticity, in which extrasynaptic receptor reservoirs supply synaptic GABAARs., Nature Communications, 6, ISSN:2041-1723

Prenatal stress is an important risk factor in schizophrenia, and the aetiological factors mediating this relationship are central to the neurodevelopmental hypothesis of schizophrenia. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) is commonly prescribed for prenatal conditions, and results in GR activation, which is part of the stress response. To investigate animal evidence for whether prenatal DEX leads to development of schizophrenia-like phenotypes, Wistar rats were prenatally exposed to DEX (0.1 mg/kg/day) between the gestational days 15 and 21, and tested in two paradigms known to be disrupted in schizophrenia patients: prepulse inhibition (PPI) and latent inhibition (LI). A cross-fostering design was used to allow dissociation of any direct prenatal effects on offspring from effects dependent on DEX exposure of the rearing dam. Pup birth weight was reduced by prenatal DEX treatment. DEX-treated dams demonstrated increased pup-directed behaviour. There were additive effects of prenatal DEX treatment and DEX treatment of rearing dam in terms of reduced body weight in adulthood. In one of two replications, PPI was increased by prenatal DEX in males only and specific to the highest prepulse intensity. There was no evidence that LI was disrupted by prenatal DEX treatment. This study does not provide support for the hypothesis that prenatal DEX exposure leads to schizophrenia-like deficits in PPI or LI, suggesting that GR prenatal programming is not a mechanism of direct relevance to the neurodevelopmental hypothesis of schizophrenia.

Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.

Depression is diagnosed on the basis of abnormal positive affects (anhedonia) and negative affects (low mood, helplessness, coping deficit, fatigue), and associated physiological abnormalities include hyperactivity of the HPA endocrine system and autonomic nervous system. Adverse early life environments, including parent-offspring emotional and physical neglect, are associated with traits of altered physiological and neurobiological function and long-term predisposition to depression. Animal studies based on early life adversity can potentially yield environmental models of the developmental behavioural neurobiology of depression. In Wistar rats, we demonstrated that isolation of pups from dam and littermates at room temperature for 4 h per day on P1-14 (early deprivation, ED) led to adulthood anhedonia-like traits of reduced motivation to obtain gustatory reward and reduced social motivation, relative to subjects left undisturbed during infancy (non-handling, NH). We hypothesized that the depression-like effects of ED would be even more pronounced and multiple in the stress hyper-responsive Fischer rat strain. The effects of ED were studied relative to NH and 15 min of daily isolation (early handling, EH). Relative to NH and EH, which exhibited remarkably similar phenotypes, ED led, principally in males, to chronic traits of: reduced motivation for and consumption of gustatory reward; increased activity in the pre-test and test phases of the forced swim test; reduced coping behaviour in an aversive environment; attenuated plasma corticosterone stress response to a normal plasma ACTH stress response; increased hypertensive response to a novel environment; and increased prefrontal cortical serotonin. High sensitivity to an aversive early environment in male Fischer rats therefore constitutes an important model for the study of affective development and its neurobiology.