The Spread of Ras Activity Triggered by Activation of a Single Dendritic Spine

Ras activity was shown to invade typically 10-20 neighboring spines in a range of 10 μm along the dendrite, whereas RhoA activity only spread 5 μm and rarely invaded neighboring spines.

“Ras activity was shown to invade typically 10–20 neighboring spines in a range of 10 μm along the dendrite, whereas RhoA activity only spread 5 μm and rarely invaded neighboring spines (Harvey et al., 2008; Murakoshi et al., 2011).”

The activation of Ras measured by FRET-FLIM was dependent on CaMKII activation, peaked later, and recovered to baseline level only after 15 min.

“The activation of Ras measured by FRET-FLIM was dependent on CaMKII activation, peaked later, and recovered to baseline level only after 15 min.”

Ras diffusion rate out of the spine was relatively fast, reaching the dendrite within seconds without leaving any immobile fraction in the spine.

“Its diffusion rate out of the spine was relatively fast, reaching the dendrite within seconds without leaving any immobile fraction in the spine (Harvey et al., 2008).”

Rho-Rock and Ras-ERK signaling pathways lower the threshold for LTP in neighboring spines.

“In addition, Rho-Rock and Ras-ERK signaling pathways lower the threshold for LTP in neighboring spines (Zhu et al., 2002; Harvey and Svoboda, 2007; Harvey et al., 2008; Lee et al., 2009).”

Both Ca2+ and Ras can regulate synaptic development and plasticity.

“Both Ca 2 þ and Ras can regulate synaptic development and plasticity (Tada and Sheng, 2006;Alvarez and Sabatini, 2007;Harvey et al, 2008).”

The paGFP-Rho GTPase decay time constants were ~10 times larger than that of cytosolic paGFP (~0.4 s) and similar to that of a constitutively active HRas mutant (~6 s).

“These values are ~10 times larger than the decay time constant of cytosolic paGFP (~0.4 s) and similar to that of a constitutively active HRas mutant (~6 s) (Fig. 3e–h)12.”

The spine volume increased rapidly by ~300% following glutamate uncaging (transient phase) and relaxed to an elevated level of 70-80% for more than 30 min (sustained phase).

“The spine volume increased rapidly by ~300% following glutamate uncaging (transient phase) and relaxed to an elevated level of 70–80% for more than 30 min (sustained phase) (Figs. 1d, 2d)12–14.”

Interactions between neighboring synapses do occur, such that intradendritic spread of activated Ras from an active synapse briefly lowers the threshold for subsequent LTP induction at neighboring synapses.

“However, interactions between neighboring synapses do occur, such that the intradendritic spread of the activated Ras from an active synapse briefly lowers the threshold for subsequent LTP induction at neighboring synapses (Harvey et al. 2008).”

This combination of techniques allowed recording activity patterns for CaMKII, Ras, RhoA and Cdc42 in dendritic spines following local glutamate uncaging.

“This combination of techniques allowed recording activity patterns for CaMKII (Lee et al., 2009), Ras (Harvey et al., 2008), RhoA and Cdc42 (Murakoshi et al., 2011) in dendritic spines following local glutamate uncaging.”

The length constant of RhoA activity spread along the dendrite was 4.5 μm.

“The length constant of spread along the dendrite was 4.5 μm (Fig. 3a, b), a value similar to that for HRas (~10 μm)12.”

The inactivation time constant is ~6 s for Cdc42 and ~30 s for RhoA, compared to 200-300 s for HRas.

“The short length constant of Cdc42 in the dendrites (1.9 μm, Fig. 3) also supports the fast inactivation of Cdc42 in the dendrite: the inactivation time constant τ is related to the length constant L and the diffusion constant D~0.6 μm2 (Ref 12) as τ = L2/D, and thus is ~6 s for Cdc42 and ~30 s for RhoA, compared to 200–300 s for HRas12.”

HRas activity spreads from stimulated spines along dendrites and into surrounding spines over ~10 μm.

“In contrast, HRas activity spreads from the stimulated spines along dendrites and into surrounding spines over ~10 μm12.”

The mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics.

“The mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics (24–26).”

Strong stimulation of single synapses causes the spread of active GTPases to neighboring spines.

“Prior work suggesting that strong stimulation of single synapses causes the spread of active GTPases to neighboring spines (24, 25) is of interest in this regard because these enzymes play critical roles in the production of stable LTP.”

These enzymes play critical roles in the production of stable LTP.

“because these enzymes play critical roles in the production of stable LTP.”