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Rebound dotentiation: long-term potentiation of inhibitory transmission at cerebellar interneuron-Purkinje cell synapses.

He, Q.; (2008) Rebound dotentiation: long-term potentiation of inhibitory transmission at cerebellar interneuron-Purkinje cell synapses. Doctoral thesis , University of London. Green open access

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Abstract

Rebound potentiation (RP) is triggered by strong climbing fibre (CF) stimulated depolarization of postsynaptic Purkinje cells (PC) in the cerebellum. Subsequent Ca2+ influx through the activation of voltage gated calcium channels (VGCC) and further Ca2+ release from intracellular stores synergise to activate Ca2+ dependent kinase pathway resulting in the manifestation of a persistent enhancement of 7 aminobutryic acid type A receptor (GABAAR) mediated current between presynaptic interneurons (IN) and postsynaptic PCs. In our study, we first discovered that different profiles for RP can be elicited using different latencies between the formation of whole cell configuration and stimulus application. This is possibly due to the disruption of the innate physiological state of the PC, but also unveiled a possible early and phase of RP. We confirmed that the induction and maintenance of RP depends on Ca2+/Camodulin-dependent kinase II (CaMKII), and revealed a role for protein tyrosine kinase (PTK) by applying a selection of inhibitors (CaMKIINtide and genistein). These two kinases may work through two inter-dependent pathways, oCaMKII mediated potentiation of inhibition appeared to be dependent on the PTK activity. Suppression of RP by inhibitors of exocytosis revealed that GABAAR insertion is the underlying mechanism of rebound potentiation, which may occur downstream of receptor phosphorylation by kinases. Using transgenic mice, we verified that the al subunit is essential for mediating the phasic inhibition observed in PC and that /32 subunit containing receptors underlie the large amplitude, fast rise time miniature inhibitory postsynaptic currents (mlPSC). They are also implicated in the induction of RP as 2-/- animals exhibited impaired RP. Thirdly, mutation of two tyrosine residues (Y365 Y367), on the y2 subunit known to be phosphorylated by PTK, delivered a rebound depression (RD) of inhibition. Hence, we conclude that these two tyrosine residues determine the polarity of the plasticity. Taken overall, the phenomenon of RP involves at least two protein kinases and it is manifest by the insertion of GABAARs at inhibitory synapses.

Type: Thesis (Doctoral)
Title: Rebound dotentiation: long-term potentiation of inhibitory transmission at cerebellar interneuron-Purkinje cell synapses.
Identifier: PQ ETD:591497
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1444195
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