Moogeh Baharnoori

Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats

The neural mechanisms by which maternal infections increase the risk for schizophrenia are poorly understood; however, animal models using maternal administration of immune activators suggest a role for cytokine imbalance in maternal/fetal compartments. As cytokines can potentially affect multiple aspects of neuronal development and the neuropathology of schizophrenia is believed to involve subtle temporo-limbic neurodevelopmental alterations, we investigated morphological development of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus in rats that were prenatally challenged with the immune activator lipopolysaccharide (LPS). Pregnant Sprague-Dawley rats were administered with LPS (at E15- E16) or saline. The brains of offspring were processed for Golgi-Cox staining at postnatal days 10, 35 and 60. Dendritic length, branching, spine density and structure were quantified using Neurolucida software. At all ages, dendritic arbor was significantly reduced in mPFC and CA1 neurons of LPS-treated animals. Dendritic length was significantly reduced in the mPFC neurons of LPS group at P10 and 35 but returned to control values at P60. Opposite pattern was observed in CA1 region of LPS animals (normal values at P10 and 35, but a reduction at P60). LPS treatment significantly altered the structure of CA1 dendritic spines at P10. Spine density was found to be significantly lower only in layer V mPFC of P60 LPS rats. The study provides the first evidence that prenatal exposure to an immune activator dynamically affects spatio-temporal development of pyramidal neurons in mPFC and hippocampal that can potentially lead to aberrant neuronal connectivity and functions of these structures.

Behavioral characterization of dysbindin-1 deficient sandy mice

Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we studied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not significantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activating effect of a low dose of d-amphetamine (2.5 mg/kg i.p.), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced locomotor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants.

Neonatal Behavioral Changes in Rats With Gestational Exposure to Lipopolysaccharide: A Prenatal Infection Model for Developmental Neuropsychiatric Disorders

Exposure to prenatal infections has been widely associated with the increased risk for neuropsychiatric disorders of developmental origin such as schizophrenia and autism. Although several behavioral and cognitive deficits have been detected during adulthood in rodent models of prenatal infections, early behavioral changes have not been well characterized. In a prenatal lipopolysaccharide (LPS) model, we have previously observed significant alterations in the neuronal cytoarchitecture during early postnatal life. In the present study, we aimed to investigate the potential effects of prenatal immune activation on early neurophenotypic presentations using a set of behavioral test battery. Female Sprague-Dawley rats were administered with 100 μg/kg LPS (intraperitoneally) at gestational days 15 and 16. During the first postnatal week, we found no significant effect on maternal behavior or mother-pup interaction by this treatment. Also, no major changes in physical developmental milestones of pups were noted from postnatal (P) days P6 to P16. Importantly, prenatal LPS-exposed pups had a significant decrease in the number and duration of ultrasonic vocalization calls at P3 and P5. Prenatal LPS treatment also led to impairments in nest-seeking behavior and odor-stroke associative learning in neonatal rats at P8 and P9. At the molecular level, we detected significant decrease in the expression of cortical 5HT1A and 5HT1B messenger RNA at P3. These data suggest that prenatal exposure to an immune activator can significantly impair the social/communicative behavior in the neonate offspring, which may be relevant to childhood and premorbid abnormalities reported in autism and schizophrenia subjects.

Effect of Maternal Lipopolysaccharide Administration on the Development of Dopaminergic Receptors and Transporter in the Rat Offspring

Epidemiological evidence supports that maternal infection during gestation are notable risk factors for developmental mental illnesses including schizophrenia and autism. In prenatal lipopolysaccharide (LPS) model of immune activation in rats, the offspring exhibit significant impairments in behaviors mediated by central dopamine (DA) system. This study aimed to examine the temporal and regional pattern of postnatal DA development in the male offspring of pregnant Sprague-Dawley rats administered with 100 µg/kg LPS or saline at gestational days 15/16. Using ligand autoradiography, D1 and D2 dopamine receptors (D1R, D2R) and dopamine transporter (DAT) binding levels were measured in the prefrontal cortex (PFC) and sub cortical regions (dorsal striatum and nucleus accumbens core and shell) at pre pubertal (P35) and post pubertal ages (P60). We found a significant decrease in D2R ligand [3H] YM-90151-2 binding in the medial PFC (mPFC) in prenatal LPS-treated animals at P35 and P60 compared to respective saline groups. The decrease in D2R levels was not observed in the striatum or accumbens of maternal LPS-treated animals. No significant changes were observed in [3H] SCH23390 binding to D1R. However, the level of [125I] RTI-121 binding to DAT was selectively reduced in the nucleus accumbens core and shell at P35 in the prenatal LPS group. Immunohistochemical analysis showed that number of D2R immunopositive cells in infralimbic/prelimbic (IL/PL) part of mPFC was significantly reduced in the LPS group at P60. Prenatal LPS treatment did not significantly affect either the total number of mature neurons or parvalbumin (PV)-immunopositive interneurons in this region. However the number of PV and D2R co-labeled neurons was significantly reduced in the IL/PL subregion of PFC of LPS treated animals. Our data suggests D2R deficit in the PFC and PV interneurons may be relevant to understanding mechanisms of cortical dysfunctions described in prenatal infection animal models as well as schizophrenia.

A sexually dichotomous, autistic‐like phenotype is induced by Group B Streptococcus maternofetal immune activation

Group B Streptococcus (GBS) is a commensal bacterium present in the lower genital tract of 15–30% of healthy pregnant women. GBS is the leading cause of chorioamnionitis and cerebral injuries in newborns, occurring most often in the absence of maternofetal pathogen translocation. Despite GBS being the most frequent bacterium colonizing pregnant women, no preclinical studies have investigated the impact of end‐gestational maternal GBS exposure on the offsprings brain development and its behavioral correlates. Our hypothesis is that GBS‐induced gestational infection/inflammation has a deleterious neurodevelopmental impact on uninfected offspring. Our goal was to study the impact of maternal GBS infection on the placental and neurodevelopmental features in the offspring using a new preclinical rat model. GBS‐exposed placentas exhibited chorioamnionitis characterized by the presence of Gram‐positive cocci and polymorphonuclear cells, with the latter being significantly more prominent in the labyrinth of male offspring. GBS‐exposed male offspring had reduced thickness of periventricular white matter. In addition, they exhibited autistic‐like behaviors, such as abnormal social interaction and communication, impaired processing of sensory information and hyperactivity. Overall, these data show for the first time that gestational exposure to GBS plays an important role in the generation of neurodevelopmental abnormalities reminiscent of human autism spectrum disorders (ASD). These results provide new evidence in favor of the role of a common and modifiable infectious/inflammatory environmental factor in human ASD pathophysiology. Autism Res 2017, 10: 233–245.

Altered expression and alpha‐1 adrenergic receptor mediated activity of protein kinase C in the prefrontal cortex of rats with neonatal ventral hippocampus lesions

The neonatal ventral hippocampus (nVH) lesion in rats captures many features of schizophrenia at the levels of behavior and neurobiological markers. We have previously reported enhanced expression of α‐1 adrenergic receptors (AR) in the prefrontal cortex (PFC) of postpubertal nVH‐lesioned rats and proposed that enhanced α‐1 AR signaling might participate in some of the behavioral abnormalities observed in the nVH‐lesioned rats. To assess the components of α‐1 adrenergic signaling in nVH‐lesiond rats, we examined prefrontal cortical expression of protein kinase C (PKC) subtypes by Western blotting and α‐1 AR‐stimulated PKC activity by in vitro enzyme assay in postpubertal animals. Neonatal VH‐lesioned animals showed significantly increased expression of membrane‐bound PKC‐α and the phosphorylated form of PKC. Cytosolic PKC‐βII and PKC‐γ expression were found to be decreased in the PFC of lesioned animals with no change in the expression of PKC‐βI either in the cytosol or membrane. PKC activity assays showed an increase in basal PKC activity in the PFC slices of nVH‐lesioned animals. Stimulation of α‐1 adrenergic receptor with different concentrations of the agonist phenylephrine (PE), while increasing PKC activity in the sham‐lesioned animals surprisingly decreased the activity in nVH‐lesioned animals. Increased basal levels as well as activity of prefrontal PKC and its anomalous regulation by α‐1 adrenergic receptors may participate in the cognitive and stress‐induced behavioral alterations in nVH‐lesioned animals. Synapse 63:1051–1059, 2009.

A case of acute cerebral gas embolism due to ingestion of hydrogen peroxide

Dear Sirs, Hydrogen peroxide (H2O2) is a potent oxidizing agent sold at variable concentrations (3–60%). Low concentrations are used as topical disinfectants and as hemostatic agents in neurosurgical procedures. Ingestion of H2O2 produces severe systemic toxicity since rapid dissociation of H2O2 to oxygen (O2) causes arterial gas embolism (AGE). Hyperbaric oxygen therapy (HBOT) is the first-line treatment. Immediate HBOT (within 7 h) is usually associated with a better outcome [1]. Here we describe a case of cerebral gas embolism (CGE) secondary to H2O2 ingestion responsive to HBOT administered 80 h after ingestion.