Akt3‐mTOR regulates hippocampal neurogenesis in adult mouse

Abstract

Akt signaling has been associated with adult neurogenesis in the hippocampal dentate gyrus (DG). We reported cognitive dysfunction in Akt3 knockout (Akt3-KO) mice with the down-regulation of mTOR activation. However, little is known about the effects of Akt3 signaling on hippocampal neurogenesis. Herein, we show that progenitor cells, neuroblasts, and mature newborn neurons in hippocampal DG expressed Akt3 protein. The Akt3 phosphorylation in hippocampal DG was increased after voluntary wheel running for 7 days in wild-type mice (running WT mice), but not in Akt3-KO mice (running Akt3-KO mice). Subsequently, we observed that the proliferation of progenitor cells was suppressed in Akt3-KO mice and the mTOR inhibitor rapamycin-treated mice, whereas enhanced in running WT mice rather than running Akt3-KO mice. Neurite growth of neuroblasts was impaired in Akt3-KO mice and rapamycin-treated mice. In contrast, neither differentiation of progenitor cells nor migrating of newly generated neurons was altered in Akt3-KO mice or running WT mice. The levels of p70S6K and 4EBP1 phosphorylation were declined in Akt3-KO mice and elevated in running WT mice depending on mTOR activation. Furthermore, telomerase activity, telomere length, and expression of telomerase reverse transcriptase (TERT) were decreased in Akt3-KO mice but increased in running WT mice rather than running Akt3-KO mice, which required the mTOR activation. The study provides in vivo evidence that Akt3-mTOR signaling plays an important role in the proliferation of progenitor cells and neurite growth through positive regulated TERT expression and activation of p70S6K and 4EBP1.

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

“…In addition, transient systemic inhibition of the mTOR pathway by rapamycin in early postnatal life resulted in abnormal proliferation, reduced progenitor cell numbers, and eventually decreased the volume of the adult dentate gyrus [ 111 ]. Similarly, treatment with rapamycin in adult mice also reduced proliferation of hippocampal progenitor cells and net neurogenesis [ 112 ]. Rapamycin also prevented increase of neurogenesis by physical activity, which is a known pro-neurogenic stimulus [ 112 ].…”

“…Similarly, treatment with rapamycin in adult mice also reduced proliferation of hippocampal progenitor cells and net neurogenesis [ 112 ]. Rapamycin also prevented increase of neurogenesis by physical activity, which is a known pro-neurogenic stimulus [ 112 ].…”

Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

“…Among candidate genes in the male population, AKT3 (serine/threonine kinase 3) is highly expressed in the brain and hippocampal pyramidal cells. Substantial evidence has implicated that AKT3 signaling is involved in cell proliferation of newborn neurons, cellular neurite outgrowth, and neurogenesis in the dentate gyrus of the hippocampus [ 45 ]. Previous studies have found that mutations of the AKT3 gene in humans are associated with a wide spectrum of developmental disorders including extreme megalocephaly [ 46 ].…”

“…The correlation between AKT3 and hippocampal nerve has been confirmed in animal experiments. For example, in mouse models, AKT3 - mammalian target of rapamycin (mTOR) signaling regulates hippocampal neurogenesis in adult mice [ 45 ], and AKT3 deficiency impairs spatial cognition and long-term potentiation of hippocampal CA1 by downregulating mTOR [ 47 ]. The studies mentioned above provided important clues for the potential biological mechanism of genes identified as affecting the development of PTSD, such as the sensitivity to stressful life events and the hippocampal nerves.…”

mTOR (Mammalian Target of Rapamycin): Hitting the Bull’s Eye for Enhancing Neurogenesis After Cerebral Ischemia?

“…There are numerous regulatory signaling pathways that are involved in cerebral ischemia-induced neurogenesis, among which, activation of mTOR (mammalian target of rapamycin) signaling may be one of these mechanisms. [23][24][25] In the past few decades, mTOR has been closely linked to tumorigenesis; however, recent research has revealed a wide range of roles of mTOR in the central nervous system and cerebrovascular diseases. [26][27][28] Maintenance of cell growth and cell cycle progression is necessary for NSC development.…”