Long-term potentiation (LTP) is a well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory. LTP has been studied in a variety of animal models and, in rodents in particular, there is now a strong body of evidence demonstrating common underlying molecular mechanisms in LTP and memory. Results are beginning to emerge from studies of neural plasticity in humans. This review will summarize findings demonstrating that synaptic LTP can be induced in human CNS tissue and that rodent and human LTP probably share similar molecular mechanisms. We will also discuss the application of non-invasive stimulation techniques to awake human subjects to induce LTP-like long-lasting changes in localized neural activity. These techniques have potential therapeutic application in manipulating neural plasticity to treat a variety of conditions, including depression, Parkinson's disease, epilepsy and neuropathic pain.

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke.

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On the evaluation o f experimental evidence 16 Putative mechanisms o f plasticity 18 Svnaptic plasticity 19 Is there experimental evidence that links LTP and memory? Are there alternative memory mechanisms? Searching for engrams On the principle o f 'mass action' Classical conditioning The conditioned eveblink Conditioned eveblinks can be acquired after decerebration The cerebellum and learning Cerebellar anatomy Microstructure and models On the Marr/Albus model 41 What are the predictions o f the Marr/Albus model? The deep nuclei may participate in learning Deep nuclear plasticity What is the evidence for deep nuclear plasticity in eveblink conditioning? Eveblink circuitry Cerebellar components are essential for eveblink conditioning The anterior interpositus is essential for eveblink conditioning Cortical lobule HVI is essential for eveblink conditioning The connections o f lobule HVI 61 An internal 'm odel' o f the conditioned eveblink can be found in the red nucleus 63 On the 'performance' debate Reversible inactivation Reversible inactivation o f the eveblink control regions is difficult but necessarv Reversible inactivation o f the cerebellar cortex The 'performance' debate is not vet resolved On the issue o f state-dependencv On the olivo-cortico-nuclear loop Consolidation On the phenomenon o f retrograde amnesia On retroactive inhibition and interference Motor learning requires consolidation Consolidation is aided bv intervals in training Conditioned eveblinks require consolidation On the experiments described within this thesis 2-location Introduction Methods Surgerv Behaviour Reversible inactivation Histology 90 Autoradiography and image analysis 92 Statistical analysis 92 Experimental design 93 Reiection o f subiects 95 Pilot study for deep nuclear placements 98 Results Studv 1 A) Post-training muscimol in lobule HVI impairs consolidation o f NM R conditioning 99 B) Post-training muscimol in the AIP does not impair consolidation o f NM R conditioning C) Post-training muscimol does not affect CR performance______________________________________ D) Rejected subjects mav confirm these findings 102 Studv 2 M uscimol does not spread ereativ over time 108 Discussion no How does muscimol in the cerebellar cortex prevent consolidation? 111 M uscimol is likely to act at synapses between inhibitory intemeurons and the other cell types 112 Is Continued neural activity required for consolidation? 113 Could cerebellar cortical muscimol affect consolidation through secondary effects on the nuclei? 114 Do post-training muscimol infusions into the cerebellar cortex completely prevent consolidation? 116 Summary 117 Results A) Most o f the antibodies reveal a homogeneous expression o f the respective epitopes 162 B) The monoclonal anti-t-PA antibodv labels discrete patches o f tissue 162 C) Western blot reveals multiple epitopes on rabbit cerebellar tissue for monoclonal anti-t-PA 165 Discussion 166 t-PA and N-CAM may be expressed at too high a constitutive level for regional variations to be identified? 166 N-CAM and t...