Project description
The role of synaptic vesicle priming in brain function, plasticity and behaviour
Synaptic plasticity, activity-dependent changes in the strength or efficacy of synaptic transmission, underlies important cognitive functions, including working memory. Research historically focused on postsynaptic changes, but plasticity occurs in presynaptic neurons as well. Neurotransmitter release at the presynaptic neuron occurs by the fusion of a pool of primed synaptic vesicles (SVs) with the plasma membrane. The role of SV priming in synaptic plasticity and brain function has not been tested due to a lack of tools. The European Research Council-funded SYNPRIME project has developed genetic models for studies of SV priming in vivo and aims to comprehensively characterise its role in synaptic efficacy in intact neural circuits.
Objective
Neuronal signalling via synaptic vesicle (SV) fusion is the fastest membrane fusion event in mammalian cells. Its speed and the ability of presynapses to sustain SV fusion at high stimulation rates are key requirements for brain function. Plastic changes of SV fusion rates have long been thought to control complex brain processes such as working memory, but the link between presynaptic plasticity and complex brain functions remains hypothetical. A key determinant of presynaptic efficacy is that synapses maintain a release-ready or primed SV pool that can be refilled rapidly. SV priming is mediated by a set of dedicated priming proteins (Munc13s, CAPSs, and accessory proteins), which are of pervasive and essential functional importance for synaptic efficacy, and - based on in vitro studies - of capacious potential to regulate exactly the type of synaptic plasticity that is associated with brain circuit characteristics involved in complex behaviours. However, this 'catholic' role of the SV priming machinery in brain function has never been tested, mainly because essential genetic models for studies in vivo have been lacking. Using (i) 4 newly generated conditional KO and KI mouse lines, (ii) 17 additional KOs/KIs (12 ours), (iii) high-end EM approaches (iv) KO-replacement strategies, (v) electrophysiological and optophysiological analyses, and (vi) behavioural studies, we will examine the SV priming machinery in intact circuits in order to (a) define the mechanisms and cell biological basis of SV priming, of its dynamics, and of defined priming-dependent synaptic plasticity states, and to (b) define the causal links between SV priming, synapse function, synaptic plasticity, circuit characteristics, and behaviour. These studies will generate a comprehensive delineation of the role of SV priming in intact neural circuits, which is not only essential for basic science but also for psychiatry, because all key priming proteins are linked to neuropsychiatric diseases.
Fields of science
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
80539 Munchen
Germany