Role of Neuronal Ras Activity in Adult Hippocampal Neurogenesis and Cognition

Abstract

Hippocampal neurogenesis in the adult mammalian brain is modulated by various signals like growth factors, hormones, neuropeptides, and neurotransmitters. All of these factors can (but not necessarily do) converge on the activation of the G protein Ras. We used a transgenic mouse model (synRas mice) expressing constitutively activated G12V-Harvey Ras selectively in differentiated neurons to investigate the possible effects onto neurogenesis. H-Ras activation in neurons attenuates hippocampal precursor cell generation at an early stage of the proliferative cascade before neuronal lineage determination occurs. Therefore it is unlikely that the transgenically activated H-Ras in neurons mediates this effect by a direct, intracellular signaling mechanism. Voluntary exercise restores neurogenesis up to wild type level presumably mediated by brain-derived neurotrophic factor. Reduced neurogenesis is linked to impairments in spatial short-term memory and object recognition, the latter can be rescued by voluntary exercise, as well. These data support the view that new cells significantly increase complexity that can be processed by the hippocampal network when experience requires high demands to associate stimuli over time and/or space.

Protection of Oligodendrocytes Through Neuronal Overexpression of the Small GTPase Ras in Hyperoxia-Induced Neonatal Brain Injury

“…Small GTPases from the Ras family are highly evolutionary conserved, molecular switches involved in important cellular responses such as proliferation, differentiation, and survival ( 28 ). We previously showed that hyperoxia reduces Ras activity and that transgenic mice overexpressing Ras under the synapsin 1 promoter ( syn Ras) to drive the selective overexpression of V12-Ha-Ras in post-mitotic neurons ( 29 ) are protected against hyperoxia-induced cellular degeneration ( 27 ).…”

“…At the molecular level, our previous work demonstrated the importance of the mitogen-activated protein kinase (MAPK) signaling pathway ( 22 , 27 ). It was shown that hyperoxia reduces Ras GTPase activity and downstream signaling pathways (e.g., phosphorylation of the extracellular regulated kinase (ERK)) ( 27 ), which modulate important cellular responses such as differentiation and survival ( 28 ). Of note, using syn Ras-transgenic mice overexpressing constitutively activated Ras ( 29 ) in the neuronal compartment, we confirmed the important involvement of this pathway demonstrating protection against oxygen-induced cell death ( 27 ).…”

A Comparison of Cognitive and Everyday Functional Performance Among Older Adults With and Without Hypertension

“…Animal studies suggest that ACE inhibitors may have a protective effect on cognition (Gard, 2008). However, the effects of either ACE inhibitors or ARBs on cognition have been controversial (Manns et al, 2011). Recent evidence suggests that the renin angiotension system plays a central role in linking hypertension to cognitive function (Hajjar et al, 2012).…”

Impact of diet-derived signaling molecules on human cognition: exploring the food–brain axis

“…For the neurogenesis signaling pathway, several sources were used. 56, 152–155 A list of signaling pathways and proteins used to construct this network is provided in Supplemental Table 1. The selection of pathways and proteins was for illustrative purposes and not intended to be exhaustive.…”