Abstract
Ca2+/CaM serine/threonine kinase II (CaMKII) is a central molecule in mechanisms of synaptic plasticity and memory. A vital feature of CaMKII in plasticity is its ability to switch to a calcium (Ca2+) independent constitutively active state after autophosphorylation at threonine 287 (T287). A second pair of sites, T306 T307 in the calmodulin (CaM) binding region once autophosphorylated, prevent subsequent CaM binding and inactivates the kinase during synaptic plasticity and memory. Recently a synaptic molecule called Ca2+/CaM-dependent serine protein kinase (CASK) has been shown to control both sets of CaMKII autophosphorylation events and hence is well poised to be a key regulator of memory. We show deletion of full length CASK or just its CaMK-like and L27 domains disrupts middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α′/β′ subset of mushroom body neurons being required for memory. Likewise directly changing the levels of CaMKII autophosphorylation in these neurons removed MTM and LTM. The requirement of CASK and CaMKII autophosphorylation was not developmental as their manipulation just in the adult α′/β′ neurons was sufficient to remove memory. Overexpression of CASK or CaMKII in the α′/β′ neurons also occluded MTM and LTM. Overexpression of either Drosophila or human CASK in the α′/β′ neurons of the CASK mutant completely rescued memory, confirming that CASK signaling in α′/β′ neurons is necessary and sufficient for Drosophila memory formation and that the neuronal function of CASK is conserved between Drosophila and human. At the cellular level CaMKII overexpression in the α′/β′ neurons increased activity dependent Ca2+ responses while reduction of CaMKII decreased it. Likewise reducing CASK or directly expressing a phosphomimetic CaMKII T287D transgene in the α′/β′ similarly decreased Ca2+ signaling. Our results are consistent with CASK regulating CaMKII autophosphorylation in a pathway required for memory formation that involves activity dependent changes in Ca2+ signaling in the α′/β′ neurons.
Highlights
Changes in neural activity and Ca2+ signaling in neural circuits of memory centers encode information during memory formation
CaM-dependent serine protein kinase (CASK) AND CaM serine/threonine kinase II (CaMKII) FUNCTIONALLY INTERACT TO REGULATE MIDDLE-TERM MEMORY FORMATION The main effect of CASK is to increase inhibitory phosphorylation of T306 T307 on endogenous CaMKII resulting in a decrease in endogenous kinase activity (Figure 1A; Lu et al, 2003; Hodge et al, 2006) and we show that mushroom body overexpression of CASK removes middle-term memory (MTM)
BODY α /β NEURONS DURING MIDDLE-TERM MEMORY FORMATION We found that CASK-β mutant flies that lack just the long isoform of CASK have reduced MTM, showing that the CaMK-like and L27 domains only present in this form of CASK (Figure 1C) are the key signaling domains required for regulating memory
Summary
Changes in neural activity and Ca2+ signaling in neural circuits of memory centers encode information during memory formation. One molecule critical for these processes is Ca2+/CaM serine/threonine kinase II (CaMKII) whose activity is acutely sensitive to changes in Ca2+ during long-term potentiation (LTP) underlying hippocampal memory formation (Lisman et al., 2002). CaMKII has been dubbed “the molecular memory switch”; because after it associates with Ca2+/CaM it undergoes a conformational change exposing a T286 on mammalian CaMKII and T287 on Drosophila CaMKII that can be autophosphorylated (Figure 1A), resulting in a Ca2+ independent constitutively active kinase (Lisman and Zhabotinsky, 2001). Pharmacological blockade or knockout of CaMKII results in mice with deficits in LTP and memory (Silva et al, 1992a,b).
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