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Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation.

Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM, Lynch G - J. Cell Biol. (2009)

Bottom Line: These experiments used this observation to uncover the synaptic processes that stabilize the potentiation effect.A search for the upstream origins of these effects showed that adenosine suppressed RhoA activity but only modestly affected Rac and Cdc42.A RhoA kinase (ROCK) inhibitor reproduced adenosine's effects on cofilin phosphorylation, spine actin polymerization, and LTP, whereas a Rac inhibitor did not.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA. crex@uci.edu

ABSTRACT
The releasable factor adenosine blocks the formation of long-term potentiation (LTP). These experiments used this observation to uncover the synaptic processes that stabilize the potentiation effect. Brief adenosine infusion blocked stimulation-induced actin polymerization within dendritic spines along with LTP itself in control rat hippocampal slices but not in those pretreated with the actin filament stabilizer jasplakinolide. Adenosine also blocked activity-driven phosphorylation of synaptic cofilin but not of synaptic p21-activated kinase (PAK). A search for the upstream origins of these effects showed that adenosine suppressed RhoA activity but only modestly affected Rac and Cdc42. A RhoA kinase (ROCK) inhibitor reproduced adenosine's effects on cofilin phosphorylation, spine actin polymerization, and LTP, whereas a Rac inhibitor did not. However, inhibitors of Rac or PAK did prolong LTP's vulnerability to reversal by latrunculin, a toxin which blocks actin filament assembly. Thus, LTP induction initiates two synaptic signaling cascades: one (RhoA-ROCK-cofilin) leads to actin polymerization, whereas the other (Rac-PAK) stabilizes the newly formed filaments.

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Schematic of processes regulating cytoskeletal dynamics during LTP stabilization. The proposed model shows signaling cascades that regulate distinct stages of dendritic spine actin reorganization. Activity-driven RhoA to cofilin signaling, leading to F-actin assembly, is rapid (∼2 min) and A1R sensitive. Evidence from other systems suggests that A1R inhibits RhoA through a GTPase-activating protein (GAP). Parallel activation of PAK via Rac is adenosine insensitive and influences later (>10 min) LTP consolidation events. The dashed PAK to LIM kinase (LIMK) arrow denotes signaling, shown in neurons and other cell systems, that does not appear to be involved in synaptic potentiation or its concomitant actin polymerization. Rather, results in this study suggest that LTP-related PAK signaling regulates proteins involved in higher order organization of the spine cytoskeleton. The independence of the described signaling pathways and their functional roles in LTP suggest that activity-induced cytoskeletal reorganization has distinct and sequential stages involving RhoA and then Rac signaling. NMDAR, NMDA receptor.
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fig8: Schematic of processes regulating cytoskeletal dynamics during LTP stabilization. The proposed model shows signaling cascades that regulate distinct stages of dendritic spine actin reorganization. Activity-driven RhoA to cofilin signaling, leading to F-actin assembly, is rapid (∼2 min) and A1R sensitive. Evidence from other systems suggests that A1R inhibits RhoA through a GTPase-activating protein (GAP). Parallel activation of PAK via Rac is adenosine insensitive and influences later (>10 min) LTP consolidation events. The dashed PAK to LIM kinase (LIMK) arrow denotes signaling, shown in neurons and other cell systems, that does not appear to be involved in synaptic potentiation or its concomitant actin polymerization. Rather, results in this study suggest that LTP-related PAK signaling regulates proteins involved in higher order organization of the spine cytoskeleton. The independence of the described signaling pathways and their functional roles in LTP suggest that activity-induced cytoskeletal reorganization has distinct and sequential stages involving RhoA and then Rac signaling. NMDAR, NMDA receptor.

Mentions: The diverse adenosine results described in the previous paragraphs help to clarify the signaling pathways used by patterned afferent activity to reorganize the spine cytoskeleton and stabilize an otherwise transient potentiation of synaptic responses. As discussed, TBS-driven cofilin phosphorylation, likely an essential step for triggering actin polymerization within spines, appears to involve an adenosine-sensitive, RhoA-initiated signaling cascade rather than Cdc42/Rac-PAK–LIM kinase signaling. In accord with this, a ROCK inhibitor, at concentrations that had no effect on pPAK, thoroughly suppressed TBS-induced increases in pCofilin+ synapses and caused LTP to gradually decay back to baseline. In contrast, inhibition of Rac or PAK activity failed to produce the type of decremental LTP found with any of several treatments that block actin polymerization. This is consistent with the finding that suppression of PAK activity by overexpressing its inhibitory subunit does not detectably affect the decay rate of hippocampal LTP (Hayashi et al., 2004). In all, the results indicate that TBS sets in motion two signaling cascades, one of which leads to the actin filament assembly needed for LTP consolidation and another which has different functions (Fig. 8).


Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation.

Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM, Lynch G - J. Cell Biol. (2009)

Schematic of processes regulating cytoskeletal dynamics during LTP stabilization. The proposed model shows signaling cascades that regulate distinct stages of dendritic spine actin reorganization. Activity-driven RhoA to cofilin signaling, leading to F-actin assembly, is rapid (∼2 min) and A1R sensitive. Evidence from other systems suggests that A1R inhibits RhoA through a GTPase-activating protein (GAP). Parallel activation of PAK via Rac is adenosine insensitive and influences later (>10 min) LTP consolidation events. The dashed PAK to LIM kinase (LIMK) arrow denotes signaling, shown in neurons and other cell systems, that does not appear to be involved in synaptic potentiation or its concomitant actin polymerization. Rather, results in this study suggest that LTP-related PAK signaling regulates proteins involved in higher order organization of the spine cytoskeleton. The independence of the described signaling pathways and their functional roles in LTP suggest that activity-induced cytoskeletal reorganization has distinct and sequential stages involving RhoA and then Rac signaling. NMDAR, NMDA receptor.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2712993&req=5

fig8: Schematic of processes regulating cytoskeletal dynamics during LTP stabilization. The proposed model shows signaling cascades that regulate distinct stages of dendritic spine actin reorganization. Activity-driven RhoA to cofilin signaling, leading to F-actin assembly, is rapid (∼2 min) and A1R sensitive. Evidence from other systems suggests that A1R inhibits RhoA through a GTPase-activating protein (GAP). Parallel activation of PAK via Rac is adenosine insensitive and influences later (>10 min) LTP consolidation events. The dashed PAK to LIM kinase (LIMK) arrow denotes signaling, shown in neurons and other cell systems, that does not appear to be involved in synaptic potentiation or its concomitant actin polymerization. Rather, results in this study suggest that LTP-related PAK signaling regulates proteins involved in higher order organization of the spine cytoskeleton. The independence of the described signaling pathways and their functional roles in LTP suggest that activity-induced cytoskeletal reorganization has distinct and sequential stages involving RhoA and then Rac signaling. NMDAR, NMDA receptor.
Mentions: The diverse adenosine results described in the previous paragraphs help to clarify the signaling pathways used by patterned afferent activity to reorganize the spine cytoskeleton and stabilize an otherwise transient potentiation of synaptic responses. As discussed, TBS-driven cofilin phosphorylation, likely an essential step for triggering actin polymerization within spines, appears to involve an adenosine-sensitive, RhoA-initiated signaling cascade rather than Cdc42/Rac-PAK–LIM kinase signaling. In accord with this, a ROCK inhibitor, at concentrations that had no effect on pPAK, thoroughly suppressed TBS-induced increases in pCofilin+ synapses and caused LTP to gradually decay back to baseline. In contrast, inhibition of Rac or PAK activity failed to produce the type of decremental LTP found with any of several treatments that block actin polymerization. This is consistent with the finding that suppression of PAK activity by overexpressing its inhibitory subunit does not detectably affect the decay rate of hippocampal LTP (Hayashi et al., 2004). In all, the results indicate that TBS sets in motion two signaling cascades, one of which leads to the actin filament assembly needed for LTP consolidation and another which has different functions (Fig. 8).

Bottom Line: These experiments used this observation to uncover the synaptic processes that stabilize the potentiation effect.A search for the upstream origins of these effects showed that adenosine suppressed RhoA activity but only modestly affected Rac and Cdc42.A RhoA kinase (ROCK) inhibitor reproduced adenosine's effects on cofilin phosphorylation, spine actin polymerization, and LTP, whereas a Rac inhibitor did not.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA. crex@uci.edu

ABSTRACT
The releasable factor adenosine blocks the formation of long-term potentiation (LTP). These experiments used this observation to uncover the synaptic processes that stabilize the potentiation effect. Brief adenosine infusion blocked stimulation-induced actin polymerization within dendritic spines along with LTP itself in control rat hippocampal slices but not in those pretreated with the actin filament stabilizer jasplakinolide. Adenosine also blocked activity-driven phosphorylation of synaptic cofilin but not of synaptic p21-activated kinase (PAK). A search for the upstream origins of these effects showed that adenosine suppressed RhoA activity but only modestly affected Rac and Cdc42. A RhoA kinase (ROCK) inhibitor reproduced adenosine's effects on cofilin phosphorylation, spine actin polymerization, and LTP, whereas a Rac inhibitor did not. However, inhibitors of Rac or PAK did prolong LTP's vulnerability to reversal by latrunculin, a toxin which blocks actin filament assembly. Thus, LTP induction initiates two synaptic signaling cascades: one (RhoA-ROCK-cofilin) leads to actin polymerization, whereas the other (Rac-PAK) stabilizes the newly formed filaments.

Show MeSH
Related in: MedlinePlus