Timing of Neurotransmitter Release

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Summary The challenge of the BRAIN Initiative and the European Human Brain Project is to determine how the billions of neurons and trillions of synapses in the human brain organize themselves into neural circuits that enable brain function. Yet the anatomical organization of neural circuits is not sufficient to understand information processing, since it is well known that neuromodulators that act outside of synapses can reconfigure patterns of neural activation by recruiting or rejecting the involvement of specific circuit components. Dynamically changing the spatial pattern of neural activation may be particularly important in the cerebellar cortex, where the precise spatial-temporal patterns of Purkinje cell (PC) activation are critical for the complex sensory-integration function of motor control. The pattern of Purkinje cell activation is controlled by olivocerebellar climbing fibers (CFs) that form powerful one-to-one glutamatergic synapses with single PCs. CFs generate a complex spike in postsynaptic PCs as well as a pause in PC simple spiking. However, CFs can also control the excitability of neighboring PCs through the activation of inhibitory interneurons. Surprisingly, CF-interneuron signaling occurs via spillover transmission in the absence of anatomically defined synaptic structures. The goal of this proposal is to determine how glutamate spillover from CFs influences cerebellar circuit function at the level of single cells, small microcircuits and cerebellar compartments. We hypothesize that CF spillover organizes the temporal-spatial pattern of neural activity at each level to expand the influence of CFs beyond the targeted PC. We will use a variety of electrophysiological, imaging and transgenic approaches to test predictions about the role of CF glutamate spillover in the spatial organization of cerebellar circuit activity. Successful completion of the proposed Aims has the potential to dramatically shift the current view of the role of CFs in cerebellar function. The conceptual novelty of this proposal stems from the demonstration that fast extrasynaptic glutamate signaling does not require morphologically-defined synapses and provides a mechanism to mediate patterned of neural activation that is regulated by spatial proximity rather than synaptic connectivity. The significance of the proposed experiments is supported by several in vivo observations suggesting that this unconventional mode of transmission from CFs contributes to the temporal- spatial pattern of PC activity in a manner that is critical for cerebellar function. Cerebellar dysfunction can lead to many human diseases involving motor control, including a family of nearly 40 conditions known as the spinocerebellar ataxias.The cerebellum is also involved in executive functions, spatial learning and memory, and emotion as well as more recently being associated with schizophrenia and autism. A more complete understanding of cerebellar circuit information processing will thus benefit a wide range of basic and clinical fields.