mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown in Adult-Born Dentate Granule Neurons

Abstract

Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyper-excitability and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA approved inhibitor, both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.

Adult Neurogenesis and Psychiatric Disorders

“…Furthermore, DISC1 knockdown specifically in adult-born dentate gyrus neurons has been shown to result in increased mTOR signaling and pronounced cognitive and affective deficits. Importantly, suppression of mTOR signaling with treatment of the Food and Drug Administration (FDA)-approved inhibitor rapamycin can rescue the behavioral deficits (Zhou et al 2013). These studies provide evidence that dysregulated adult neurogenesis may contribute to the cognitive impairments seen in psychiatric diseases, and that the cognitive deficits in animal models can be at least partially rescued by restoration of neurogenesis in the adult brain, suggesting that adult neurogenesis is a viable therapeutic target.…”

“…Therefore, this study showed an interaction between local neural activity and a schizophrenia susceptibility gene, a gene-environment interaction in the regulation of neuronal development in the mammalian brain (Kim et al 2012). Intriguingly, hippocampal-dependent cognitive and affective deficits in mice resulting from DISC1 deficiency, specifically in newborn granule neurons of the hippocampus, were partially rescued by rapamycin (Zhou et al 2013). Taken together, these studies suggest that the mental disorder susceptibility gene DISC1 regulates discrete components of neurogenesis and neuronal development through distinct signaling pathways, which is consistent with the neurodevelopmental hypothesis.…”

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

“…On a molecular level, knockdown of Disc1 results in increased mTOR signaling. Moreover, Disc1 knockdown induces cognitive and affective deficits and behavioral abnormalities are reversed by pharmacological inhibition of the mTOR pathway (Zhou et al 2013a).…”

Trim9Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

“…Aberrant adult neurogenesis is linked to neurological disorders (Deng et al, 2010;Christian et al, 2014). For instance, deletion of Pten or DISC1 knockdown is associated with aberrant adult-born granule cell morphology linked to epilepsy or behavioral deficits (Deng et al, 2009;Pun et al, 2012;Zhou et al, 2013). Although aberrant development of adult-born neurons may disrupt behavior and elicit pathology, the molecular factors that regulate development, morphogenesis, and integration of adult-born hippocampal neurons are largely unknown.…”