Neuronal activation of Ras regulates synaptic connectivity

Abstract

A synRas mouse model was used expressing constitutively activated Ha-Ras (Val12 mutation) in neurons to investigate the role of Ras-MAPkinase signalling for neuronal connectivity in adult brain. Expression of the transgene in the cortex of these mice starts after neuronal differentiation is completed and allows to directly investigate the effects of enhanced Ras activity in differentiated neurons. Activation of Ha-Ras induced an increase in soma size which was sensitive to MEK inhibitor in postnatal organotypic cultures. Adult cortical pyramidal neurons showed complex structural rearrangements associated with an increased size and ramification of dendritic arborization. Dendritic spine density was elevated and correlated with a twofold increase in number of synapses. In acute brain slices of the somatosensory and of the visual cortex, extracellular field potentials were recorded from layer II/III neurons. The input-output relation of synaptically evoked field potentials revealed a significantly higher basal excitability of the transgenic mice cortex compared to wild-type animals. In whole cell patch clamp preparations, the frequency of AMPA receptor-mediated spontaneous excitatory postsynaptic currents was increased while the ratio between NMDA and AMPA-receptor mediated signal amplitude was unchanged. A pronounced depression of paired pulse facilitation indicated that Ras contributes to changes at the presynaptic site. Furthermore, synRas mice showed an increased synaptic long-term potentiation, which was sensitive to blockers of NMDA-receptors and of MEK. We conclude that neuronal Ras is a common switch of plasticity in adult mammalian brain sculpturing neuronal architecture and synaptic connectivity in concert with tuning synaptic efficacy.

MicroRNA-134 activity in somatostatin interneurons regulates H-Ras localization by repressing the palmitoylation enzyme, DHHC9

“…This modification is required for directing H-Ras to the neuronal membrane, where it mediates morphological changes and may participate in LTP and memory formation (16). Our studies indicate that in SST + neurons, DHHC9 is down-regulated by neuronal activity through a pathway that involves miR-134.…”

Plk2 Raps up Ras to subdue synapses

“…7,8 Ras also drives synaptic delivery of AMPARs [8][9][10][11] as well as production of dendritic protrusions/ spines. 12,13 In contrast, Rap typically favors However, a deeper analysis suggests another reason Plk2 may target multiple GAPs and GEFs, beyond the requirements of simple efficacy. RNA interference knockdown and overexpression experiments revealed that each Plk2 substrate actually affects relatively specific aspects of dendritic spine morphology.…”

The Ras-GRF1 Exchange Factor Coordinates Activation of H-Ras and Rac1 to Control Neuronal Morphology

“…Mm (Martegani et al, 1992;Cen et al, 1993), contains both a CDC25 domain that confers exchange factor activity toward Ras (Cen et al, 1993;Wei et al, 1994) and a Dbl homology (DH)/plekstrin homology (PH) region that can act as an exchange factor for Rac1 (Kiyono et al, 1999) link the activation of Ras in general (Manabe et al, 2000;Arendt et al, 2004) and via Ras-GRF1 in particular (Krapivinsky et al, 2003;Schmitt et al, 2005) to molecular and cellular events, such as long-term potentiation and synaptic remodeling, which are thought to underlie memory. Genetic evidence, both from mouse models (Brambilla et al, 1997;Giese et al, 2001;Tian et al, 2004) and human disorders (Weeber et al, 2002), also supports such a link.…”

“…It is highly expressed at the synapses of neurons in the CNS (Sturani et al, 1997). There is considerable evidence to link the activation of Ras in general (Manabe et al, 2000;Arendt et al, 2004) and via Ras-GRF1 in particular (Krapivinsky et al, 2003;Schmitt et al, 2005) to molecular and cellular events, such as long-term potentiation and synaptic remodeling, which are thought to underlie memory. Genetic evidence, both from mouse models (Brambilla et al, 1997;Giese et al, 2001;Tian et al, 2004) and human disorders (Weeber et al, 2002), also supports such a link.…”

“…The conversion between these states is governed by several groups of enzymes, including the exchange factors (GEFs) that catalyze the release of GDP and subsequent binding of GTP to activate these proteins, and the GAPs, that greatly stimulate the endogenous GTPase activity of Ras proteins and so stimulate their inactivation (Boguski and McCormick, 1993). Physiological control of the switch can reside in regulation of either the relevant GEF or GAP (Bernards and Settleman, 2004), but increasing evidence suggests that the very complex, multidomain structure of the Ras-GEF proteins provides the possibility that they integrate multiple signals to determine the activation state of their target GTPase Sprang, 2001;Quilliam et al, 2002).The Ras-GRF1 exchange factor (Shou et al, 1992), which is also termed CDC25Mm (Martegani et al, 1992;Cen et al, 1993), contains both a CDC25 domain that confers exchange factor activity toward Ras (Cen et al, 1993;Wei et al, 1994) and a Dbl homology (DH)/plekstrin homology (PH) region that can act as an exchange factor for Rac1 (Kiyono et al, 1999) link the activation of Ras in general (Manabe et al, 2000;Arendt et al, 2004) and via Ras-GRF1 in particular (Krapivinsky et al, 2003;Schmitt et al, 2005) to molecular and cellular events, such as long-term potentiation and synaptic remodeling, which are thought to underlie memory. Genetic evidence, both from mouse models (Brambilla et al, 1997;Giese et al, 2001;Tian et al, 2004) and human disorders (Weeber et al, 2002), also supports such a link.…”