Abstract
Fear conditioning, a behavioral model for studying fear-related disorders, is believed to be formed by alterations of synaptic efficacy mediated by changes in synaptic transmission and neuronal morphology in lateral amygdala (LA). Rac GTPase and its downstream effector p21-activated kinase (PAK) are involved in such key neuronal functions. Here we show that optical activation of Rac1 GTPase using photoactivatable form of Rac1 (PA-Rac1) in amygdala led to phosphorylation of PAK and inhibition of long-term but not short-term auditory fear conditioning memory formation. Activation of PA-Rac1 in LA one day after fear conditioning had no effect on long-term fear memory tested 24 hrs after PA-Rac1 activation. Inhibition of PAK in LA by microinjection of the PAK inhibitor IPA-3 30 minutes before fear conditioning enhanced long-term but not short-term fear memory formation. Our results demonstrate that photoactivation of Rac1 GTPase in lateral amygdala impairs fear memory formation. Moreover, Rac1 effector PAK activity during fear conditioning constrains the formation of fear memory in LA. Thus, Rac GTPase and PAK proteins may serve as targets for treatment of fear and anxiety disorders.
Highlights
Experiencing a traumatic event may lead to the development of fear-related disorders
We show that light stimulation leads to increased staining of phospho-p21-activated kinase (PAK) in cells in amygdala expressing the mCherry-PA-Rac[1] compared to animals that were not subjected to light (p < 0.02)
In this study we examined whether Rac GTPase activation and PAK inhibition affect short- and long-term fear memory formation in lateral amygdala
Summary
Experiencing a traumatic event may lead to the development of fear-related disorders. Rac[1] GTPase and its downstream effector PAK have been shown to be involved in neuronal morphogenesis and synaptic transmission. Rac[1] activation in LA may affect fear memory formation and be a useful tool for intervening with fearful memory consolidation Further evidence supporting this hypothesis are the observations that actin cytoskeleton dynamics in LA are needed for long-term fear memory formation[27,28,29] and that changes in neuronal morphology in LA, known to be mediated by actin such as spine morphogenesis, are involved in fear memory formation[30,31]. We further investigated the roles of PAK in fear memory formation
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