Duguid, Ian Charles; (2001) Inhibitory synaptic plasticity in the cerebellum. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Learning and memory within the brain are thought to be based on long lasting changes in synaptic efficacy. Purkinje neurones, which focus their output on descending projection pathways and constitute the sole inhibitory output from the cerebellum, display two forms of synaptic plasticity termed 'depolarisation-induced suppression of inhibition' (DSI) and 'rebound potentiation' (RP). Purkinje neurone depolarisation induces a rapid rise in [Ca2+ ]I triggering both the release of a retrograde transmitter and activation of a variety of protein kinases. The phenomena of DSI underlies a transient (lasting <60s) decrease in the mean frequency of mIPSCs, occurring immediately after stimulus cessation, while RP manifests itself as a robust increase in the mean amplitude of spontaneous and miniature inhibitory postsynaptic currents (IPSCs). The present study examined the relationship between pre- and postsynaptic plasticity during the induction phase of DSI and rebound potentiation in cultured cerebellar Purkinje neurones. Depolarisation caused an immediate decrease in the frequency of mIPSCs (lasting ~40s), followed by a transient increase in mIPSC frequency lasting approximately 5 minutes before recovering. A robust potentiation of the mean mIPSC amplitude was observed throughout all experiments and persisted for the duration of recording. The initial frequency decrease (DSI), was abolished by a specific group II mGluR antagonist, LY 341495, while the subsequent transient frequency potentiation was abolished by the specific N-methyl-D-aspartate receptor (NMDAR) antagonist, d-APV. Removal of extracellular sodium, the main current carrying ion through NMDARs, mimicked the application of d-APV by abolishing the frequency potentiation while having no effect on the induction of DSI. Immunocytochemical staining of mixed cerebellar preparations identified cerebellar basket/stellate cells as displaying immunoreactivity for NMDAR NR1 subunits but not mGluR2/3 at putative presynaptic release sites. These results provide the first evidence for, 1) the involvement of presynaptic NMDARs in the transient enhancement of GABA release during rebound potentiation and 2) the possibility that a novel group II mGluR splice variant/subtype underlies the induction of cerebellar DSI. A model is proposed to explain the relationship between DSI and rebound potentiation.

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