Fukunaga, I.; (2008) Cellular identity of cerebellar memory. Doctoral thesis , University of London.

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Abstract

The cerebellum is essential for some forms of motor learning and storage of motor memories. The simple organization of the cerebellum provides special opportunities to analyse mechanisms underlying learning and memory in a real neural network. A dominant hypothesis of cerebellar function is one based on suggestions by Marr and Albus, where Purkinje cell responses to parallel fibre inputs are modified under climbing fibre control. A candidate cellular mechanism is a long-term depression of parallel fibre-Purkinje cell synapses (pf-PC LTD) seen, in vitro, after conjunctive activation of parallel and climbing fibres. The associative and persistent nature of pf- PC LTD suggests that it may underlie behavioural forms of cerebellum-dependent learning. Activation of the metabotropic glutamate receptor type 1 (mGlui receptor) is critical for the induction of pf-PC LTD. If pf-PC LTD underlies learning, then blocking this receptor should lead to impairment of cerebellum-dependent learning. The studies described here test the role of the mGlui receptor in one form of cerebellum- dependent associative learning. Chapters 2 and 3 describe slice electrophysiological experiments that assess the mGlul antagonists CPCCOEt, YM-298198 and JNJ16259685. CPCCOEt was found to have a non-specific action, while YM-298198 and JNJ16259685 were found to be very potent and highly specific. Chapter 4 describes the effects of cerebellar infusions of JNJ 16259685 on classical conditioning of the rabbit nictitating membrane response and reveals that conditioning was not impaired. The result suggests there could be dissociation between pf-PC LTD and cerebellar learning. It is known that pf-PC LTD in vitro may not be a single phenomenon since it can be induced with a range of protocols that can differ significantly from the normal physiology. Thus, there may be a form of pf-PC LTD in vivo that is relatively independent of mGlui receptor function. Alternatively, behavioural learning may depend upon plasticities involving other neuronal types in the cerebellar cortex.

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