Ramos Allegre Branco, T; (2007) A study of the determinants of release probability in hippocampal synapses. Doctoral thesis , UCL (University College London).

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Abstract

The release of neurotransmitter at a synapse is a stochastic process, such that the arrival of an action potential triggers vesicle fusion with a lim ited probability (pr). Although pr is a fundamental parameter in denning synaptic efficacy, it is not uniform across all synapses, and the mechanisms by which a given synapse sets its basal release probability are unknown. This study employed FM-dye imaging, paired whole-cell recordings and se rial ultrastructural analysis with 3D reconstruction to address this question. Optical measurements of pr at single synapses were made in small networks of cultured hippocampal neurons, and suggest a new model of pr regulation ' whereby release probability is set locally by the dendrite through a nega tive feedback mechanism. In synaptically connected pairs of neurons, a high resolution spatial analysis reveals that neighbouring synapses on the same dendritic branch show very similar release probabilities, even though the connection overall has a broad distribution of pr. Moreover, pr is negatively correlated with the number of synapses made between the axon and the den dritic branch. Increasing network activity elicits a homeostatic decrease in pr that is dependent on dendritic depolarization, and imposing a spatially uniform input to the dendrite significantly reduces the variability in pr. Fur thermore, manipulating the activity of a single dendritic branch leads to a spatially selective decrease in pr. These results indicate that local dendritic activity is the major determinant of basal release probability, and theoreti cal simulations suggest that this retrograde regulation provides a means to maintain synchronously activated synapses in their operational range.

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