The synaptic basis of vestibular processing in cerebellar granule cells.
Doctoral thesis, UCL (University College London).
The synapse is the fundamental element of neuronal communication. However, how sensory stimuli are representated at the level of single synapses has to date been difficult to assess due to poor stimulus control and / or the large number of synapses a typical neuron receives. Here I have addressed this question by taking advantage of cerebellar granule cells (GCs) as they provide an ideal model system for two reasons. First, they receive on average only 4 excitatory inputs from mossy fibres (MFs), making it possible to distinguish single synaptic inputs. Second, GCs in the flocculus receive prominent vestibular input, which constitutes a well-defined sensory stimulus with a low dimensional stimulus space. Since whole cell recordings in vivo are typically carried out under general anaesthesia for recording stability, I first characterised the effects of two commonly used injectable anaesthetics, pentobarbitone and ketamine, on fast synaptic transmission at the MF-GC synapse in vitro. While pentobarbitone depressed the EPSC amplitude and speeded the EPSC decay phase over relevant concentrations, ketamine (in combination with xylazine) did not impact on (primarily AMPA receptor mediated) fast synaptic transmission and thus qualified as a suitable anaesthetic to study synaptic signalling at this synapse in vivo. Under ketamine/xylazine anaesthesia, I performed in vivo whole-cell voltage-clamp recordings from GCs in the mouse cerebellar flocculus to characterise fast synaptic transmission at the MF-GC synapse in response to vestibular stimulation. In the absence of vestibular stimulation, vestibular-sensitive GCs showed spontaneously occuring EPSCs. Vestibular stimulation around the earth-vertical axis in the dark resulted in a bidirectional modulation of the EPSC frequency, which correlated linearly with the angular velocity, rather than with position or acceleration. A lack of synaptic short-term dynamics ensured that velocity was linearly representated not only in terms of frequency, but also in terms of excitatory charge transfer at the GC membrane. In a subset of GCs distinct MF inputs could be reliably distinguished based on their EPSC amplitude and kinetics. In those cases, only a subset of inputs was modulated by vestibular stimulation while the remaining inputs were insensitve to horizontal rotation. This suggests that despite receiving very few inputs GCs can have multidimensional receptive fields. Using a Bayesian approach we examined the capacity of EPSC trains in GCs to report the velocity stimulus that evoked them, in order to estimate the size of the population of MF inputs/GCs required to reach a behaviourally relevant resolution of the velocity representation. While synaptic activity in a single GC could report the presence and direction of movement, the error in the stimulus reconstruction was large. However, with increasing GC number the velocity estimate improved in accuracy and reliability in a logarithmic fashion, and an ensemble of as few as 100 GCs provided an accuracy of 4.8 º/s, approaching the psychophysical limit. Purkinje cells integrating information from a vast number of GCs therefore should be able to achieve a high resolution representation of sensory stimuli within a single cell with capacity to spare for multimodal integration.
|Title:||The synaptic basis of vestibular processing in cerebellar granule cells|
|Additional information:||Authorisation for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology|
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