Ultrastructure-function properties of recycling vesicle pools in native central synapses

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The basic function of the brain is to process information: receiving sensory input, generating appropriate responses and learning/remembering. The information is encoded in the form of small electrical signals, which are passed between specialized cells called neurons wired up together to form circuits. The way the information transfers from neuron to neuron is closely controlled but also adjustable, and these properties underlie the computational power of the brain. Currently, we only have a basic comprehension of transmission; determining how neurons regulate and vary information flow is central to understanding how the brain works and is a major goal in neuroscience research.Most information transmission occurs at chemical synapses, specialized contact points where two neurons - a signalling and receiving neuron - come close together. The signalling neuron has a cluster of spherical structures called vesicles, each containing a chemical signal. Electrical activity triggers this neuron to mobilize its vesicles and release their chemical contents towards the part of the synapse belonging to the receiving neuron. This target structure has special receptors which respond to the chemical and bring about a change in the electrical activity of the neuron. In this way, information is moved from one neuron to the next.Why does the process involve an intermediate chemical transmission step? This allows synapses to control and adjust the information transferred. Such a feature sets networks of neurons apart from digital circuits in computers, allowing them to adapt to changes in operational demand or even 'rewire' themselves to support learning.How is this flexible nature of transmission achieved? This is a key issue in neuroscience. One possibility is that transmitter-containing vesicles themselves are involved. Most mammalian synapses have ~250 vesicles. Surprisingly, only a fraction of these are available to release their chemical signal. If the number of releasable vesicles could be varied at each synapse, this would offer a simple mechanism to allow adjustments in the information transferred. Alternatively, the physical positioning of vesicles in synapses - allowing them to be released more or less efficiently - could be an important factor. These ideas have been difficult to address, particularly in real brain circuits, because of the technical challenges in monitoring small synapses and the nanometre scale of the vesicles.The objective of this grant is to explore these key ideas. We will use fluorescence imaging methods to directly visualize the dynamic properties of single synapses in rat brain tissue. Also, using a novel approach we will uniquely view individual releasable vesicles with ultrastructural resolution. We will characterize the numbers of functional vesicles in different synapses in large neuronal networks, and determine what molecular pathways and other properties of circuits set these parameters. By building 3d reconstructions of vesicle populations at a synapse, we will also investigate how releasable vesicles are arranged, and examine how these properties influence synaptic performance. We will also define the characteristics of vesicle organization in synapses driven by visual input in behaving animals, allowing us to explore synaptic properties in relation to real sensory signals. Additionally, we will test whether forms of electrical input, corresponding to activity experienced by neurons during learning, bring about changes in the properties of vesicle organization. Addressing these questions is a major step in understanding fundamental brain function. Moreover, synaptic transmission is a major target for neurological diseases, such as Alzheimer's. Vesicle populations represent obvious potential substrates that could underlie synaptic failure; in the future, characterizing the mechanisms that regulate their function could offer promising new strategies for disease-related drug therapies.