Abstract
Adult hippocampal neurogenesis, the constitutive generation of new granule cells in the dentate gyrus of the mature brain, is a robust model of neural development and its dysregulation has been implicated in the pathogenesis of psychiatric and neurological disorders. Previous studies in mice have shown that altered expression of Disrupted-In-Schizophrenia 1 (Disc1), the mouse homolog of a risk gene for major psychiatric disorders, results in several distinct morphological phenotypes during neuronal development. Although there are advantages to using rats over mice for neurophysiological studies, genetic manipulations have not been widely utilized in rat models. Here, we used a retroviral-mediated approach to knockdown DISC1 expression in dividing cells in the rat dentate gyrus and characterized the morphological development of adult-born granule neurons. Consistent with earlier findings in mice, we show that DISC1 knockdown in adult-born dentate granule cells in rats resulted in accelerated dendritic growth, soma hypertrophy, ectopic dendrites, and mispositioning of new granule cells due to overextended migration. Our study thus demonstrates that the Disc1 genetic manipulation approach used in prior mouse studies is feasible in rats and that there is a conserved biological function of this gene across species. Extending gene-based studies of adult hippocampal neurogenesis from mice to rats will allow for the development of additional models that may be more amenable to behavioral and in vivo electrophysiological investigations. These models, in turn, can generate additional insight into the systems-level mechanisms of how risk genes for complex psychiatric disorders may impact adult neurogenesis and hippocampal function.
Highlights
Significant progress has been made over the past several years to identify genetic disruptions that increase susceptibility to psychiatric disorders
To investigate risk gene-mediated changes in adult neurogenesis in a model system that is highly amenable to physiological and behavioral experiments, we examined the effects of Disrupted-In-Schizophrenia 1 (DISC1) knockdown in neural progenitors in the adult rat hippocampus
We used a retrovirus-mediated birth dating and genetic manipulation approach to knock down DISC1 expression in the adult rat dentate gyrus
Summary
Significant progress has been made over the past several years to identify genetic disruptions that increase susceptibility to psychiatric disorders. Very little is known about how most of these genes contribute to the dysregulation of cellular processes or can influence the integrity of distributed neural systems One such gene of interest is Disrupted-In-Schizophrenia 1 (DISC1), DISC1 regulates neurogenesis in rats which was initially identified at the breakpoint of a chromosomal translocation t(1;11)(q42.1;q14.3) that co-segregates with schizophrenia (Millar et al, 2000; Blackwood et al, 2001) and mood disorders (Hamshere et al, 2005; Hashimoto et al, 2006). DISC1 is broadly expressed in many brain regions during embryonic development and promotes cell proliferation, migration, and neurite outgrowth (Bradshaw et al, 2011) It interacts with GSK3beta to regulate neural progenitor proliferation (Kamiya et al, 2005; Shinoda et al, 2007; Mao et al, 2009). Dysregulation of adult neurogenesis has been implicated in several psychiatric and neurological disorders, but the causal relevance and potential mechanisms are not well understood (Kitabatake et al, 2007; Christian et al, 2010, 2014)
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