Publications (19) View all
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Article: Effects of risperidone treatment in adolescence on hippocampal neurogenesis, parvalbumin expression, and vascularization following prenatal immune activation in rats.
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ABSTRACT: Maternal infection in pregnancy is an environmental risk factor for the development of schizophrenia and related disorders in the offspring, and this association is recapitulated in animal models using gestational infection or immune stimulation. We have recently shown that behavioral abnormalities and altered hippocampal morphology emerging in adult offspring of dams treated with the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) are prevented by treatment with the atypical antipsychotic drug risperidone (RIS) in adolescence. Here we used a battery of cellular markers and Nissl stain to morphometrically analyze different hippocampal cell populations in the offspring of poly I:C and saline-treated mothers that received saline or RIS in adolescence, at different time points of postnatal development. We report that impaired neurogenesis, disturbed micro-vascularization and loss of parvalbumin-expressing hippocampal interneurons, are found in the offspring of poly I:C-treated dams. Most, but not all, of these neuropathological changes are not present in poly I:C offspring that had been treated with RIS. These effects may be part of the complex processes underlying the capacity of RIS treatment in adolescence to prevent structural and behavioral abnormalities deficits in the poly I:C offspring.Brain Behavior and Immunity 11/2011; 26(2):353-63. · 4.72 Impact Factor -
Article: Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat.
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ABSTRACT: Environmental or genetic disturbances of early brain development are suggested to underlie the pathophysiology of several adult-onset neuropsychiatric disorders. We traced the developmental trajectories of brain structural and behavioral abnormalities from adolescence to young adulthood in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (poly-I:C) in pregnancy. Pregnant rats were injected on gestational day 15 with poly-I:C (4 mg/kg) or saline. Volumes of lateral ventricles, hippocampus, striatum, and prefrontal cortex in male and female offspring were assessed longitudinally at postnatal days 35, 46, 56, 70, and 90 using in vivo magnetic resonance imaging. At parallel time windows, groups of offspring from the same litters underwent behavioral testing (latent inhibition and amphetamine-induced activity) and magnetic resonance imaging (cross-sectional assessment). The specific developmental trajectories of volumetric changes in both control and poly-I:C offspring were region-, age-, and sex-specific, but overall, poly-I:C offspring had smaller volumes of the hippocampus, striatum and prefrontal cortex, and larger ventricular volume. Structural pathology in different regions had different times of onset and was gradually accompanied by behavioral deficits, disrupted latent inhibition, and excessive amphetamine-induced activity. The onset of structural frontocortical and ventricular abnormalities and behavioral abnormalities was delayed in females. In both sexes, hippocampal and striatal volume reduction predated the appearance of behavioral abnormalities. Prenatal insult interferes with postnatal brain maturation, which in turn may result in behavioral abnormalities.Biological psychiatry 08/2011; 70(9):842-51. · 8.93 Impact Factor -
Article: Tracing the development of psychosis and its prevention: what can be learned from animal models.
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ABSTRACT: Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C- and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34-47 and PND 48-61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age- and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34-47). Administration at a later window, PNDs 48-61, exerted sex-, region- and drug- specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented.Neuropharmacology 06/2011; 62(3):1273-89. · 4.81 Impact Factor -
Article: Dynamic changes in neurexins' alternative splicing: role of Rho-associated protein kinases and relevance to memory formation.
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ABSTRACT: The three neurexins genes (NRXN1/2/3) encode polymorphic synaptic membrane proteins that are involved in cognitive functioning. Neurexins' selectivity of function is presumably conferred through differential use of 2 promoters and 5 alternative splicing sites (SS#1/2/3/4/5). In day-old rat brain neurons grown in culture, activation (depolarization) induces reversible, calcium dependent, repression of NRXN2α SS#3 insert. The effects of depolarization on NRXN1/2/3α splicing and biochemical pathways mediating them were further studied in these neurons. NRXN1/2/3α splicing in the course of memory formation in vivo was also explored, using fear conditioning paradigm in rats in which the animals were trained to associate an aversive stimulus (electrical shock) with a neutral context (a tone), resulting in the expression of fear responses to the neutral context.In the cultured neurons depolarization induced, beside NRXN2α SS#3, repression of SS#3 and SS#4 exons in NRXN3α but not NRXN1α. The repressions were mediated by the calcium/protein kinase C/Rho-associated protein kinase (ROCK) pathway. Fear conditioning induced significant and transient repressions of the NRXN1/2/3α SS#4 exons in the rat hippocampus. ROCK inhibition prior to training attenuated the behavioral fear response, the NRXN1/2/3α splicing repressions and subsequent recovery and the levels of excitatory (PSD95) and inhibitory (gephyrin) synaptic proteins in the hippocampus. No such effects were observed in the prefrontal cortex. Significant correlations existed between the fear response and hippocampal NRXN3α and NRXN2α SS#4 inserts as well as PSD95 protein levels. Hippocampal NRXN1α SS#4 insert and gephyrin levels did not correlate with the behavioral response but were negatively correlated with each other.These results show for the first time dynamic, experience related changes in NRXN1/2/3α alternative splicing in the rat brain and a role for ROCK in them. Specific neurexins' transcripts may be involved in synaptic remodeling occurring at an intermediate (hours) time scale in the course of memory formation.PLoS ONE 01/2011; 6(4):e18579. · 4.09 Impact Factor -
Article: Risperidone administered during asymptomatic period of adolescence prevents the emergence of brain structural pathology and behavioral abnormalities in an animal model of schizophrenia.
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ABSTRACT: Schizophrenia is a disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations precede onset of symptoms, raising a question of whether schizophrenia can be prevented. Early treatment with atypical antipsychotics may reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We have recently shown, using in vivo structural magnetic resonance imaging, that treatment with the atypical antipsychotic clozapine during an asymptomatic period of adolescence prevents the emergence of schizophrenia-like brain structural abnormalities in adult rats exposed to prenatal immune challenge, in parallel to preventing behavioral abnormalities. Here we assessed the preventive efficacy of the atypical antipsychotic risperidone (RIS). Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Their male offspring received daily RIS (0.045 or 1.2 mg/kg) or vehicle injection in peri-adolescence (postnatal days [PND] 34-47). Structural brain changes and behavior were assessed at adulthood (from PND 90). Adult offspring of poly I:C-treated dams exhibited hallmark structural abnormalities associated with schizophrenia, enlarged lateral ventricles and smaller hippocampus. Both of these abnormalities were absent in the offspring of poly I:C dams that received RIS at peri-adolescence. This was paralleled by prevention of schizophrenia-like behavioral abnormalities, attentional deficit, and hypersensitivity to amphetamine in these offspring. We conclude that pharmacological intervention during peri-adolescence can prevent the emergence of behavioral abnormalities and brain structural pathology resulting from in utero insult. Furthermore, highly selective 5HT(2A) receptor antagonists may be promising targets for psychosis prevention.Schizophrenia Bulletin 05/2010; 37(6):1257-69. · 8.80 Impact Factor
