CASK and CaMKII function in Drosophila memory

Bilal R Malik,James J L Hodge

doi:10.3389/fnins.2014.00178

Abstract

Calcium (Ca2+) and Calmodulin (CaM)-dependent serine/threonine kinase II (CaMKII) plays a central role in synaptic plasticity and memory due to its ability to phosphorylate itself and regulate its own kinase activity. Autophosphorylation at threonine 287 (T287) switches CaMKII to a Ca2+ independent and constitutively active state replicated by overexpression of a phosphomimetic CaMKII-T287D transgene or blocked by expression of a T287A transgene. A second pair of sites, T306 T307 in the CaM binding region once autophosphorylated, prevents CaM binding and inactivates the kinase during synaptic plasticity and memory, and can be blocked by a TT306/7AA transgene. Recently the synaptic scaffolding molecule called CASK (Ca2+/CaM-associated serine kinase) has been shown to control both sets of CaMKII autophosphorylation events during neuronal growth, Ca2+ signaling and memory in Drosophila. Deletion of either full length CASK or just its CaMK-like and L27 domains removed middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α′/ß′ mushroom body neurons being required for memory. In a similar manner directly changing the levels of CaMKII autophosphorylation (T287D, T287A, or TT306/7AA) in the α′/ß′ neurons also removed MTM and LTM. In the CASK null mutant expression of either the Drosophila or human CASK transgene in the α′/ß′ neurons was found to completely rescue 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. Expression of human CASK in Drosophila also rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation. Mutations in human CASK have recently been shown to result in intellectual disability and neurological defects suggesting a role in plasticity and learning possibly via regulation of CaMKII autophosphorylation.

Highlights

Information is encoded and stored in response to changes in neural activity and Ca2+ signaling in circuits underlying memory formation in the brain
Consistent with this, we found that direct overexpression of CaMKII-T287D in the α /β neurons caused a similar reduction in middle-term memory (MTM) as knocking-down CASK in the same neurons (Figure 2E), while CaMKII-T287D expression in the α/β and γ neurons had no effect
Consistent with these studies we showed mushroom body expression of CaMKIIRNAi only affected long-term memory (LTM) (Malik et al, 2013). In addition this is the only CASK or CaMKII transgene that gave a memory phenotype when expressed in the α/β or γ neuron, suggesting LTM is sensitive and requires a certain baseline level of CaMKII activity in every type of mushroom body neuron in order to form LTM. This is in contrast to α/β or γ neuron expression www.frontiersin.org of CaMKII-T287D, T287A, and TT306/7AA that had no effect on LTM (Figure 2E), possibly because the endogenous CaMKII in α/β or γ neuron maybe sufficient to support enough of the required autophosphorylation activity to generate LTM

Summary

CASK and CaMKII function in Drosophila memory

Edited by: Claude Desplan, New York University, USA Reviewed by: Andre Fiala, Georg-August-Universität Göttingen, Germany Alex C. Calcium (Ca2+) and Calmodulin (CaM)-dependent serine/threonine kinase II (CaMKII) plays a central role in synaptic plasticity and memory due to its ability to phosphorylate itself and regulate its own kinase activity. The synaptic scaffolding molecule called CASK (Ca2+/CaM-associated serine kinase) has been shown to control both sets of CaMKII autophosphorylation events during neuronal growth, Ca2+ signaling and memory in Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may regulate CaMKII autophosphorylation. Mutations in human CASK have recently been shown to result in intellectual disability and neurological defects suggesting a role in plasticity and learning possibly via regulation of CaMKII autophosphorylation

INTRODUCTION

Malik and Hodge

Findings

Research question