Characterization of behavioral, signaling and cytokine alterations in a rat neurodevelopmental model for schizophrenia, and their reversal by the 5-HT₆ receptor antagonist SB-399885

Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT₆ receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister-hooded rats (weaned on post-natal day 21-24 and housed individually or in groups of 3-4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a two week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimination (NOD), pre-pulse inhibition of acoustic startle and acquisition, retention and extinction of a conditioned freezing response (CFR) were assessed. Tissue was collected 24 h after the final injection for immunohistochemistry, reverse-phase protein microarray and western blotting. Isolation rearing impaired NOD and cue-mediated CFR, decreased cell proliferation within the dentate gyrus, and elevated hippocampal TNFα levels and Cdc42 expression. SB-399885 reversed the NOD deficit and partially normalized CFR and cell proliferation. These effects were accompanied by altered expression of several members of the c-Jun N-terminal Kinase (JNK) and p38 MAPK signaling pathways (including TAK1, MKK4 and STAT3). Although JNK and p38 themselves were unaltered at this time point hippocampal TAK1 expression and phosphorylation correlated with visual recognition memory in the NOD task. Continued use of this neurodevelopmental model could further elucidate the neurobiology of schizophrenia and aid assessment of novel therapies for drug-resistant cognitive symptoms

Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes

Cortical GABAergic dysfunction may underlie the pathophysiology of psychiatric disorders, including schizophrenia. Here, we characterized a mouse strain in which the essential NR1 subunit of the NMDA receptor (NMDAR) was selectively eliminated in 40–50% of cortical and hippocampal interneurons in early postnatal development. Consistent with the NMDAR hypofunction theory of schizophrenia, distinct schizophrenia-related symptoms emerged after adolescence, including novelty-induced hyperlocomotion, mating and nest-building deficits, as well as anhedonia-like and anxiety-like behaviors. Many of these behaviors were exacerbated by social isolation stress. Social memory, spatial working memory and prepulse inhibition were also impaired. Reduced expression of glutamic acid decarboxylase 67 and parvalbumin was accompanied by disinhibition of cortical excitatory neurons and reduced neuronal synchrony. Postadolescent deletion of NR1 did not result in such abnormalities. These findings suggest that early postnatal inhibition of NMDAR activity in corticolimbic GABAergic interneurons contributes to the pathophysiology of schizophrenia-related disorders.Fil: Belforte, Juan Emilio. Wayne State University; Estados Unidos. National Institute of Mental Health; Estados Unidos. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zsiros, Veronika. National Institute of Mental Health; Estados UnidosFil: Sklar, Elyse R. National Institute of Mental Health; Estados Unidos. Wayne State University; Estados UnidosFil: Jiang, Zhihong. National Institute of Mental Health; Estados UnidosFil: Yu, Gu. University of Maryland; Estados UnidosFil: Li, Yuqing. University of Alabama at Birmingahm; Estados UnidosFil: Quinlan, Elizabeth M. University of Maryland; Estados UnidosFil: Nakazawa, Kazu. National Institute of Mental Health; Estados Unido

Global mindset and the internationalization of small firms: The importance of the characteristics of entrepreneurs

Despite being a relatively new concept, the importance of the global mindset is already well-documented. So far research has primarily focused on multinational companies and therefore the operationalization of the concept is still a work in progress. Recognizing the importance of entrepreneurs in small companies, yet mindful of the gaps that exist, this paper addresses the factors that constitute the global mindset and their influence on the internationalization of small Portuguese companies. Using information-processing theory through a quantitative, surveybased study and Structural Equation Modeling (SEM), the results show the importance of the characteristics of both entrepreneurs and firms in explaining the global mindset, and confirm the impact they have on internationalization behavior. The entrepreneur’s level of education, their satisfaction with company performance in the domestic market and the potential for growth in the domestic market all affect the global mindset model. The conclusions are useful for entrepreneurs and national authorities aiming to successfully implement internationalization practices, given the role of the global mindset in exploring global business opportunities and in the global success of companies. Replication of the research in different contexts is essential for the wider generalization of the results.info:eu-repo/semantics/publishedVersio