A Role for the PI-3 Kinase Signaling Pathway in Fear Conditioning and Synaptic Plasticity in the Amygdala

Abstract

Western blot analysis of neuronal tissues taken from fear-conditioned rats showed a selective activation of phosphatidylinositol 3-kinase (PI-3 kinase) in the amygdala. PI-3 kinase was also activated in response to long-term potentiation (LTP)-inducing tetanic stimulation. PI-3 kinase inhibitors blocked tetanus-induced LTP as well as PI-3 kinase activation. In parallel, these inhibitors interfered with long-term fear memory while leaving short-term memory intact. Tetanus and forskolin-induced activation of mitogen-activated protein kinase (MAPK) was blocked by PI-3 kinase inhibitors, which also inhibited cAMP response element binding protein (CREB) phosphorylation. These results provide novel evidence of a requirement of PI-3 kinase activation in the amygdala for synaptic plasticity and memory consolidation, and this activation may occur at a point upstream of MAPK activation.

Mechanisms of fear extinction

“…PI3K has been implicated in the acquisition of long-term fear memory. 290,291 Studies employing measurement of pAkt levels within the BLA following extinction training have produced very inconsistent results. Cannich et al 288 reported no significant increase in pAkt in the BLA of extinguished wild-type or cannabinoid receptor knockout (CB1À/À) mice relative to nonextinguished controls, although the ratio of pAkt levels in extinguished vs nonextinguished animals was significantly greater in the knockouts (which exhibit a profound extinction impairment) than in the wild types.…”

FoxO6 regulates memory consolidation and synaptic function

“…It is also possible that lowering insulin/IGF signaling ''sensitizes'' the organism to signals that transiently activate PI3K signaling. The capacity to retain transient waves of insulin/IGF/PI3K signaling activity (leading to FoxO activity oscillations) may be needed during memory retention and retrieval (Lin et al 2001;Opazo et al 2003;Chen et al 2005;Horwood et al 2006). Indeed, recent studies have also shown that injection of an IGF family member, IGF2, into the hippocampus after training enhanced memory (Chen et al 2011) and that injection of IGF2 after extinction trials facilitated extinction of memory (Agis-Balboa et al 2011).…”

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

“…AKT1, although ubiquitous, is highly expressed in brain, hence critically involved in neuronal survival, but also important for neuronal excitability and synaptic plasticity by directly regulating GABA-A receptor mediated synaptic inhibition (9). It appears to be involved in neurodevelopment and working memory formation, domains potentially impaired in schizophrenia (10,11).…”