Abstract
Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neurodevelopmental processing in the pathophysiological progress of schizophrenia has not been well investigated. Here in this study, by using the rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, we aimed to examine whether the postnatal neurogenesis might be involved in the development of schizophrenia-like pathology. Through the comprehensive behavioral analyses of multiple core symptoms of schizophrenia at different developmental stages (6-, 9-, and 12-weeks after birth) of the affected offspring, we found a delayed onset of schizophrenia-like behaviors in poly (I:C) animals through the development. Meanwhile, there is an age-dependent alteration of postnatal neurogenesis in the poly (I:C) animals along different development stages by which the aberrant dendritic elaboration functionally correlated with the schizophrenia-like symptoms in 9-week-old of age for the animals. Interestingly, increase in the neurogenesis during a critical period of neurodevelopment exacerbates the schizophrenia-like pathology. Conversely, temporal suppression of aberrant postnatal neurogenesis during the same period of neurodevelopment ameliorates the occurrence of schizophrenia-like symptoms. Together, these findings strongly suggested the aberrant dendritic growth of postnatal neurogenesis during the critical time window of development is essential for controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic.
Highlights
Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the general population worldwide (Perala et al, 2007; Global Burden of Disease Study 2013 Collaborators, 2015)
By using the rodent model of schizophrenia through maternal immune activation with poly (I:C), we first confirmed the presence of core symptoms of schizophrenia-like pathology at different neurodevelopmental stages of the animals
Since we found the pharmacological stimulation of neurogenesis by memantine treatment during the critical period of neurodevelopment significantly exacerbates the core symptoms of schizophrenia-like pathology in the poly (I:C) group of animals, we investigated if the dendritic development of the newly generated neurons might be affected by memantine treatment
Summary
Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the general population worldwide (Perala et al, 2007; Global Burden of Disease Study 2013 Collaborators, 2015). The pathology of schizophrenia is characterized by positive symptoms (such as hallucinations, delusions, and thought disorder), negative symptoms (less emotional responsiveness and reduced motivations), and dysfunction of cognitive flexibility. Since the pathology of schizophrenia typically appears during the late adolescence or early adulthood, it has long been regarded as a neurodevelopmental disorder (Garey, 2010). Recently it become generally accepted that neurogenesis is not restricted to prenatal stage but is a continuing process for the postnatal period, including the adolescence and even the adult. The new neurons produced continuously at restricted brain regions including the subventricular zone and the subgranular zone of the hippocampal dentate gyrus throughout the whole life (Altman, 1969; Gage, 2002; Zhao et al, 2008)
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