Rheb1 mediates DISC1-dependent regulation of new neuron development in the adult hippocampus.

A large number of susceptibility genes have been implicated in psychiatric disorders with a developmental origin, yet their biological roles and signaling mechanisms in neurodevelopment are largely unknown. Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for several major psychiatric disorders, regulates the development of newborn neurons in the adult hippocampus. Systemic pharmacological inhibition of mTOR signaling with rapamycin has been shown to rescue DISC1 deficiency-induced neurodevelopmental defects, as well as cognitive and affective deficits. Whether mTOR signaling plays a cell-autonomous and/or non-cell-autonomous role in DISC1-dependent regulation of neuronal development is not clear. Here we provide genetic evidence that hyper-activation of mTOR activator Rheb1 (Ras homolog enriched in brain 1) in newborn neurons recapitulates DISC1 deficiency-induced neurodevelopmental defects, including neuronal morphogenesis and migration. We further show that genetic deletion of Rheb1 rescues those defects in a cell-autonomous fashion in developing newborn neurons in the adult hippocampus. Our genetic and functional studies demonstrate that Rheb1 acts as a key mediator of DISC1-dependent regulation of mTOR signaling and neuronal development during adult hippocampal neurogenesis.

Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.

Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis.

D-aspartic acid is abundant in the developing brain. We have identified and cloned mammalian aspartate racemase (DR), which converts L-aspartate to D-aspartate and colocalizes with D-aspartate in the brain and neuroendocrine tissues. Depletion of DR by retrovirus-mediated expression of short-hairpin RNA in newborn neurons of the adult hippocampus elicits profound defects in the dendritic development and survival of newborn neurons and survival. Because D-aspartate is a potential endogenous ligand for NMDA receptors, the loss of which elicits a phenotype resembling DR depletion, D-aspartate may function as a modulator of adult neurogenesis.

DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.

Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.

Development of neural stem cell in the adult brain.

New neurons are continuously generated in the dentate gyrus of the mammalian hippocampus and in the subventricular zone of the lateral ventricles throughout life. The origin of these new neurons is believed to be from multipotent adult neural stem cells. Aided by new methodologies, significant progress has been made in the characterization of neural stem cells and their development in the adult brain. Recent studies have also begun to reveal essential extrinsic and intrinsic molecular mechanisms that govern sequential steps of adult neurogenesis in the hippocampus and subventricular zone/olfactory bulb, from proliferation and fate specification of neural progenitors to maturation, navigation, and synaptic integration of the neuronal progeny. Future identification of molecular mechanisms and physiological functions of adult neurogenesis will provide further insight into the plasticity and regenerative capacity of the mature central nervous system.

Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.

Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.