Neuronal Ras activation inhibits adult hippocampal progenitor cell division and impairs spatial short‐term memory

Abstract

A large number of endogenous and exogenous factors have been identified to upregulate and downregulate proliferation, differentiation and/or survival of newborn cells in the adult hippocampus. For studying neuronal mechanisms mediating the impact of those factors, we used a transgenic synRas mouse model expressing constitutively activated Valin12-Harvey Ras selectively in differentiated neurons. BrdU injections showed significantly reduced proliferation of new cells within the adult hippocampus of transgenic animals compared with their wild-type siblings. In contrast, the relative survival of newborn cells was increased in synRas mice, although this effect did not fully compensate for diminished proliferation. Inhibition of progenitor cell proliferation and enhancement of cellular survival were more pronounced in males compared with females. Double labelling and doublecortin immunostaining verified that specifically newborn neurons were decreased in synRas mice. Reduced cell generation was observed already 2 h after BrdU pulse injections, identifying an early precursor cell population as target of the inhibitory transgene effect. Differences in proliferation remained stable after 24 h and were specific for the subgranular zone of the dentate gyrus, as subventricular cell generation was not affected supporting a non-cell autonomous effect on neural hippocampal progenitors. Transgene expression only starts with synaptic differentiation and therefore reduced proliferation must represent an indirect secondary consequence of synRas activity in differentiated neurons. This was associated with impaired spatial short-term memory capacities as observed in a radial maze paradigm. Our data suggest that constantly high Ras activity in differentiated neurons downregulates hippocampal precursor cell generation in the neuronal lineage, but is modulated by sex-dependent factors.

Role of Neuronal Ras Activity in Adult Hippocampal Neurogenesis and Cognition

“…This has been demonstrated by BrdU-injections that revealed a lower number of BrdU-labeled cells 24 h after the last of 12 injections. A specific reduction of the newborn neuronal population has been confirmed by double labeling with neuron- and glia-specific markers and by a smaller number of doublecortin-positive cells (Table 1; Lafenêtre et al, 2010; Manns et al, 2010). This effect is exclusive for the adult hippocampus since generation of new cells within the subventricular zone is not affected (Manns et al, 2010).…”

“…A specific reduction of the newborn neuronal population has been confirmed by double labeling with neuron- and glia-specific markers and by a smaller number of doublecortin-positive cells (Table 1; Lafenêtre et al, 2010; Manns et al, 2010). This effect is exclusive for the adult hippocampus since generation of new cells within the subventricular zone is not affected (Manns et al, 2010). Additionally, doublecortin immunolabeling also demonstrated impaired dendritic differentiation in neuronal precursor cells of synRas mice as indicated by smaller dendritic lengths and a lower number of dendritic segments (Lafenêtre et al, 2010).…”

“… [1] Manns et al (2010), [2] Lafenêtre et al (2010), [3] Heumann et al (2000), [4] Arendt et al (2004), [5] Seeger et al (2005), [6] Gärtner et al (2005), [7] Gärtner et al (2004), [8] Patz et al (2009) .…”

“…SynRas mice display reduced neurogenesis primarily resulting from a diminished proliferation rate of the progenitor cell population (Lafenêtre et al, 2010; Manns et al, 2010). This has been demonstrated by BrdU-injections that revealed a lower number of BrdU-labeled cells 24 h after the last of 12 injections.…”

Ras Activity Tunes the Period and Modulates the Entrainment of the Suprachiasmatic Clock

“…It has been recently shown that the consolidation of long-term recognition memory is a circadian-regulated process, mediated by the Ras-inhibitory protein SCOP (62). On the other hand, synRas mice showed impaired spatial short-term memory associated also with a reduced proliferation of newborn cells in the dentate gyrus of the hippocampus (63, 64) and decreased short-term recognition memory (65, 66). All these studies suggest that modulation of Ras activity is critical for memory performance, but a question remains as to whether and how circadian regulation of Ras is associated in this process.…”