Mitchell, Simon James; (2001) Modulation of transmitter release at a glomerular synapse in the central nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The regulation of synaptic transmission is thought to be important for information processing and learning and memory. Synaptically-released transmitter can activate presynaptic receptors located at the same synapse to mediate homosynaptic modulation and/or spillover to neighbouring synapses to mediate heterosynaptic modulation. I investigated the properties of heterosynaptic modulation of transmitter release via metabotropic receptors at the cerebellar glomerulus using electrophysiological and modelling techniques. Evoked inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) were recorded at 37°C from granule cells in rat cerebellar slices. Pharmacological activation of metabotropic glutamate receptors (mGluRs) on Golgi cell axons depressed evoked IPSCs by 75±5% (mean±sem; n=6) at 0.2 Hz, by inhibiting the release of GABA. The level of inhibition reduced with increasing stimulation frequency. Synaptically-released glutamate via mossy fibre stimulation (MFS), also induced disinhibition (50±7%; n=6). The magnitude of disinhibition increased with increasing MFS frequency and did not show appreciable accommodation throughout a 5 s period of MFS. Similarly, pharmacological activation of metabotropic GABA receptors (GABAB-Rs) depressed evoked glutamate released from mossy fibres by 54±5% (1 Hz; n=12). Glutamate release inhibition was significant at 0.1-1 Hz, but not at 10-100 Hz MFS. Physiologically-released GABA from spontaneously active Golgi cells did not depress the evoked EPSC at 37°C unless a GABA uptake blocker was present, suggesting that GABA uptake maintains ambient GABA levels below that required for GABAB-R activation. However, stimulation of a single Golgi cell axon at 50 Hz depressed the EPSC by 24±3% (n=19). Heterosynaptic GABAB-R-mediated EPSC inhibition was dependent on MFS frequency, consistent with the pharmacological data. I investigated the effects of heterosynaptic modulation on synaptic integration using an integrate and-fire model with granule cell properties. Activation of mGluRs enhanced spiking driven by high frequency mossy fibres, increasing the gain of these inputs. GABAB-R activation suppressed spiking driven by mossy fibres firing at low frequency, thereby acting as a high-pass filter. Heterosynaptic modulation is likely to locally enhance contrast between granule cells with different numbers of high-frequency mossy fibres. The mechanisms reported in this thesis might shape how sensory information carried by mossy fibres is processed at the input level, thereby determining the pattern of activation of Purkinje cell, the output neurone of the cerebellar cortex.

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