Intrahippocampal Wortmannin Infusion Enhances Long-Term Spatial and Contextual Memories

Dash, Pramod K.; Mach, Sara A.; Blum, Sonja; Moore, Anthony N.

doi:10.1101/lm.50002

Cited by 17 publications

(12 citation statements)

References 54 publications

(62 reference statements)

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“…Therefore, mTOR regulates protein turnover in neurons by functioning at the intersection between protein synthesis and degradation. Pharmacological reagents, such as rapamycin or WRT, modulate mTOR activity and are known to have roles in synaptic plasticity and memory (Dash et al, 2002;Cammalleri et al, 2003;Hoeffer et al, 2008). Their effects have been explained only on the basis of local translation, although these reagents are common autophagy modulators.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Stimulation Induces Autophagy in Hippocampal Neurons That Is Involved in AMPA Receptor Degradation after Chemical Long-Term Depression

Shehata

Matsumura²,

Okubo-Suzuki³

et al. 2012

Journal of Neuroscience

249

224

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Many studies have reported the roles played by regulated proteolysis in synaptic plasticity and memory, but the role of autophagy in neurons remains unclear. In mammalian cells, autophagy functions in the clearance of long-lived proteins and organelles and in adaptation to starvation. In neurons, although autophagy-related proteins (ATGs) are highly expressed, autophagic activity markers, autophagosome (AP) number, and light chain protein 3-II (LC3-II) are low compared with other cell types. In contrast, conditional knock-out of ATG5 or ATG7 in mouse brain causes neurodegeneration and behavioral deficits. Therefore, this study aimed to test whether autophagy is especially regulated in neurons to adapt to brain functions. In cultured rat hippocampal neurons, we found that KCl depolarization transiently increased LC3-II and AP number, which was partially inhibited with APV, an NMDA receptor (NMDAR) inhibitor. Brief low-dose NMDA, a model of chemical long-term depression (chem-LTD), increased LC3-II with a time course coincident with Akt and mammalian target of rapamycin (mTOR) dephosphorylation and degradation of GluR1, an AMPA receptor (AMPAR) subunit. Downstream of NMDAR, the protein phosphatase 1 inhibitor okadaic acid, PTEN inhibitor bpV(HOpic), autophagy inhibitor wortmannin, and short hairpin RNA-mediated knockdown of ATG7 blocked chem-LTD-induced autophagy and partially recovered GluR1 levels. After chem-LTD, GFP-LC3 puncta increased in spines and in dendrites when AP-lysosome fusion was blocked. These results indicate that neuronal stimulation induces NMDAR-dependent autophagy through PI3K-Akt-mTOR pathway inhibition, which may function in AMPAR degradation, thus suggesting autophagy as a contributor to NMDAR-dependent synaptic plasticity and brain functions.

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Section: Discussionmentioning

confidence: 99%

Neuronal Stimulation Induces Autophagy in Hippocampal Neurons That Is Involved in AMPA Receptor Degradation after Chemical Long-Term Depression

Shehata

Matsumura²,

Okubo-Suzuki³

et al. 2012

Journal of Neuroscience

249

224

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“…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.…”

Section: Neurotransmitter Systemsmentioning

confidence: 99%

Mechanisms of fear extinction

2006

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Excessive fear and anxiety are hallmarks of a variety of disabling anxiety disorders that affect millions of people throughout the world. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear and anxiety is attracting increasing interest in the research community. In the laboratory, fear inhibition most often is studied through a procedure in which a previously fear conditioned organism is exposed to a fear-eliciting cue in the absence of any aversive event. This procedure results in a decline in conditioned fear responses that is attributed to a process called fear extinction. Extensive empirical work by behavioral psychologists has revealed basic behavioral characteristics of extinction, and theoretical accounts have emphasized extinction as a form of inhibitory learning as opposed to an erasure of acquired fear. Guided by this work, neuroscientists have begun to dissect the neural mechanisms involved, including the regions in which extinction-related plasticity occurs and the cellular and molecular processes that are engaged. The present paper will cover behavioral, theoretical and neurobiological work, and will conclude with a discussion of clinical implications. Molecular Psychiatry (2007) 12, 120-150.

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“…Additionally, trkB KI mutants with blocked activation of PI3K/Akt signaling have impaired cued fear LTM formation, while contextual fear LTM is spared (Musumeci et al 2009). Further, hippocampal PI3K/Akt signaling is not known to have a role in spatial memory formation (Dash et al 2002;Horwood et al 2006;Chao et al 2007). Thus, in the amygdala PI3K/Akt signaling is important for LTM formation, while this pathway may not be required for hippocampal LTM formation.…”

Section: Pi3kmentioning

confidence: 99%

The roles of protein kinases in learning and memory

2013

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In the adult mammalian brain, more than 250 protein kinases are expressed, but only a few of these kinases are currently known to enable learning and memory. Based on this information it appears that learning and memory-related kinases either impact on synaptic transmission by altering ion channel properties or ion channel density, or regulate gene expression and protein synthesis causing structural changes at existing synapses as well as synaptogenesis. Here, we review the roles of these kinases in short-term memory formation, memory consolidation, memory storage, retrieval, reconsolidation, and extinction. Specifically, we discuss the roles of calcium/calmodulin-dependent kinase II (CaMKII

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Intrahippocampal Wortmannin Infusion Enhances Long-Term Spatial and Contextual Memories

Cited by 17 publications

References 54 publications

Neuronal Stimulation Induces Autophagy in Hippocampal Neurons That Is Involved in AMPA Receptor Degradation after Chemical Long-Term Depression

Neuronal Stimulation Induces Autophagy in Hippocampal Neurons That Is Involved in AMPA Receptor Degradation after Chemical Long-Term Depression

Mechanisms of fear extinction

The roles of protein kinases in learning and memory

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