Intermediate-Term Memory for Site-Specific Sensitization inAplysiaIs Maintained by Persistent Activation of Protein Kinase C

Abstract

Recent studies of long-term synaptic plasticity and long-term memory have demonstrated that the same functional endpoint, such as long-term potentiation, can be induced through distinct signaling pathways engaged by different patterns of stimulation. A critical question raised by these studies is whether different induction pathways either converge onto a common molecular mechanism or engage different molecular cascades for the maintenance of long-term plasticity. We directly examined this issue in the context of memory for sensitization in the marine mollusk Aplysia. In this system, training with a single tail shock normally induces short-term memory (Ͻ30 min) for sensitization of tail-elicited siphon withdrawal, whereas repeated spaced shocks induce both intermediate-term memory (ITM) (Ͼ90 min) and long-term memory (Ͼ24 hr). We now show that a single tail shock can also induce ITM that is expressed selectively at the trained site (site-specific ITM). Although phenotypically similar to the form of ITM induced by repeated trials, the mechanisms by which site-specific ITM is induced and maintained are distinct. Unlike repeated-trial ITM, site-specific ITM requires neither protein synthesis nor PKA activity for induction or maintenance. Rather, the induction of site-specific ITM requires calpain-dependent proteolysis of activated PKC, yielding a persistently active PKC catalytic fragment (PKM) that also serves to maintain the memory in the intermediateterm temporal domain. Thus, two unique forms of ITM that have different induction requirements also use distinct molecular mechanisms for their maintenance.

Serotonin–mushroom body circuit modulating the formation of anesthesia-resistant memory in Drosophila

“…Atypical PKM appears to act downstream of Radish, because induction of atypical PKM can rescue the radish mutant phenotype (42). Persistent activation of PKCs during memory formation has been shown in other animals, including honey bee and Aplysia (43,44). Together, these data indicate that, through activation of d5HT1A receptor, 5HT released from the DPM neurons sets Radish and atypical PKM in action to form ARM in the α/β neurons.…”

Serotonin-Induced Cleavage of the Atypical Protein Kinase C Apl III inAplysia

“…We have proposed that cleavage by calpain is the mechanism of PKM formation. Previous evidence in favor of this includes the blockade of some forms of plasticity by calpain inhibitors (Sutton et al, 2004;Villareal et al, 2009) and evidence that mRFP-PKC Apl III can be cleaved by calpain when overexpressed .…”

Protein Kinase C Regulates Local Synthesis and Secretion of a Neuropeptide Required for Activity-Dependent Long-Term Synaptic Plasticity

“…The kinases phosphorylate both local cytoplasmic substrates (Schuster et al, 1985;Bailey et al, 1997;Martin et al, 1997;Michael et al, 1998;Angers et al, 2002;Liu et al, 2004) and transcription factors in the sensory neurons (Dash et al, 1990;Bacskai et al, 1993;Alberini et al, 1994;Martin et al, 1997;Bartsch et al, 1998;Yamamoto et al, 1999;Purcell et al, 2003). Protein kinase C (PKC) activity is enhanced by 5-HT (Sacktor and Schwartz, 1990;Sossin and Schwartz, 1992) and participates in both short-and intermediate-term facilitation (ITF) (Sugita et al, 1992(Sugita et al, , 1997Wu et al, 1995;Sutton and Carew, 2000;Manseau et al, 2001;Sutton et al, 2004), but its role in nonassociative LTF is not clear (Sossin et al, 1994;Wu et al, 1995). Activation of MAPK in sensory neurons is mediated by 5-HT-induced increases in the synthesis, secretion, and autocrine action of sensorin, the sensory beginning at 30 min after tetanus plus 5-HT (Liu et al, 2004;Hu et al, 2006).…”

“…The persistent activation of type II PKA by cAMP by either five applications of 5-HT (Bernier et al, 1982;Greenberg et al, 1987;Muller and Carew, 1998;Liu et al, 2004) or pairing tetanus plus 5-HT (Abrams et al, 1991(Abrams et al, , 1998 could phosphorylate key proteins that enhance the secretion of the neuropeptide (Goodman et al, 1996;Han et al, 1999;Jovanovic et al, 2000;Angers et al, 2002). Persistent activation of PKC at synaptic terminals of sensory neurons (Sossin et al, 1994;Sutton et al, 2000Sutton et al, , 2004Zhao et al, 2006) may also lead to the phosphorylation of synaptic proteins necessary for secretion of neuropeptides (Nakhost et al, 2003;Houeland et al, 2007;Sieburth et al, 2007) or the phosphorylation of cytoskeletal proteins or other substrates that regulate the recruitment of neuropeptide-containing vesicles to appropriate positions near the plasma membrane for subsequent release (Knox et al, 1992;Nakhost et al, 1998Nakhost et al, , 2002White et al, 1998;Smith, 1999;Nagy et al, 2002;Gruenbaum et al, 2003). Inhibition of either kinase immediately after stimulation blocks both release and LTF.…”