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The role of PDZ scaffold CASK and CaMKII signaling in synaptic plasticity and learning

Reference	BB/G008973/1
Principal Investigator / Supervisor	Dr James Hodge
Co-Investigators / Co-Supervisors
Institution	University of Bristol
Department	Physiology and Pharmacology
Funding type	Research
Value (£)	432,783
Status	Completed
Type	Research Grant
Start date	01/06/2009
End date	31/05/2012
Duration	36 months

Abstract

CaMKII is an abundant kinase in the brain, constituting 1-2% of its total protein and is the main protein in the hippocampal postsynaptic density. Once activated by increased Ca2+, CaMKII is able to cause a switch in its own activity (called T286 autophosphorylation), which allows it to have increased enzymatic activity independent of elevated Ca2+. This special ability of CaMKII has been called the 'molecular memory switch' and is required for LTP and learning. In addition CaMKII can mediate other changes that occur during synaptic plasticity and memory formation. These CaMKII mediated changes in synaptic plasticity are required for learning and memory in most animals including Drosophila. Recently we and others have shown that when Ca2+ is low (i.e. at quiescent synapses) CaMKII can regulate its own activity by a second mechanism (called T306 autophosphorylation) and this tends to inactivate CaMKII even if postsynaptic Ca2+ levels rise. We found a novel protein that interacts with CaMKII at fly synapses called CASK which is able to increase the ability of CaMKII to undergo T306 autophosphorylation and by doing so interferes with the ability of CaMKII to undergo T286 autophosphorylation, This interaction would be predicted to interfere with LTP-like events and learning. Therefore in this proposal we wish to determine the role of CASK and its regulation of CaMKII activity in synaptic plasticity underlying learning using the genetically and experimentally tractable Drosophila system. To achieve this we will make new fly CaMKII and CASK mutants and determine their effect together or alone on changes in synaptic Ca2+ signaling, synaptic growth and activity-dependent changes in T286 and T306 autophosphorylation. Whenever possible we will measure these changes in parts of the fly brain that mediate learning and using acute changes in electrical activity or learning stimuli. Finally we will determine the role of CaMKII and CASK in associative learning and memory.

Summary

The aim of this proposal is to better understand the molecular mechanisms by which memories are formed in the brain. Research into memory is particularly important as it gives us our sense of identity. Deficits in learning and memory occur in many diseases, injuries and during aging. Identifying the key molecules involved in these processes, will help reveal targets for new therapeutic interventions to reverse the devastating consequences of memory loss, this research is particularly important for our aging population. The brain consists of many cells or neurons that communicate via connections called synapses. Information flows through neurons via small electrical impulses, a bit like a computer. At most synapses these electrical impulses cause release of chemicals that bind to the output neuron causing it to become more excitable and propagate the electrical impulse to the next neuron in the circuit. The brain also stores information during learning and retrieves it as memory. There are special parts of the brain for learning e.g. the hippocampus. When an animal experiences learning stimuli there is a persistent increase in synaptic transmission between hippocampal neurons called Long Term Potentiation (LTP), this increase continues after the original stimulus is removed and is a synaptic mechanism for learning. These long-term changes in synaptic activity can cause increases in synaptic growth and connections between neurons, a process called synaptic plasticity that is thought to be a synaptic mechanism of memory. LTP and learning is initiated by calcium (Ca2+) entering the neuron and activating an enzyme called Ca2+ responsive kinase (CaMKII). CaMKII is abundant in the brain, constituting 1-2% of its total protein and is one of the main synaptic proteins. Once activated by increased Ca2+, CaMKII is able to cause a switch in its own activity so that it remains active even after Ca2+ has gone down. This special ability of CaMKII to maintain its own activity has been termed 'the molecular memory switch' and is required for both LTP and learning. CaMKII then regulates the activity of other proteins at the synapse that together maintain the increased synaptic transmission of LTP. In addition CaMKII activity can lead to many of the other changes occurring during synaptic plasticity and memory formation. These CaMKII mediated changes in synaptic plasticity are required for learning and memory in most animals including Drosophila. Although fruitflies are small they are smart, for instance they can land on the ceiling and detect that fruit in your fruit bowl has gone off before you can. In this proposal we wish to study CaMKII-mediated synaptic mechanisms of learning and memory further taking advantage of powerful genetics of Drosophila. One important question we wish to answer is: How is CaMKII's activity regulated and localised at synapses during learning? We have found that in flies like in mammals, at inactive synapses with low levels of Ca2+, CaMKII can regulate its own activity by a second mechanism that tends to inactivate CaMKII. We found a novel protein that interacts with CaMKII at fly synapses called CASK that tends to inactivate CaMKII thereby disrupting the ability of CaMKII to undergo the molecular memory switch. These changes would be predicted to interfere with LTP-like events and learning and memory. Therefore in this proposal we wish to determine the direct role of CASK and CaMKII activity in synaptic plasticity underlying learning and memory using flies. To achieve this we will make new fly CaMKII and CASK mutants and determine the effect of these together or alone on a range of synaptic events in parts of the fly brain that mediate learning and memory. Finally we will determine the role of CaMKII and CASK in the fly's learning and memory behaviour. This will provide important insight into how brains have evolved their huge capacity to acquire and store information.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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