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The Journal of Neuroscience, August 13, 2003, 23(19):7368-7375

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Absence of Tissue Plasminogen Activator Gene or Activity Impairs Mouse Cerebellar Motor Learning

Nicholas W. Seeds, Mark E. Basham, and Jayne E. Ferguson

Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80262

Motor learning is thought to involve modulation of synaptic inputs in the cerebellar cortex, including granule neuron/Purkinje neuron contacts. During a complex motor task requiring mice to walk across irregularly spaced pegs, cerebellar granule neurons show a rapid and transient induction of mRNA for the extracellular protease tissue plasminogen activator (tPA). This induction of tPA mRNA is cerebellar specific, is not seen in the cerebella of exercised or stressed animals, and is distinct from simple performance phenomena. Knock-out mice lacking the tPA gene show a significant reduction in both rate and extent of learning. Furthermore, blocking tPA activity during training dramatically impaired motor learning. Thus, tPA plays an important role in motor learning, in which tPA may facilitate remodeling of the active synaptic zone.

Key words: tPA mRNA; protease inhibitor; PAI-1; granule neuron; synaptic plasticity; memory

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Received Apr. 3, 2003; revised Jun. 5, 2003; accepted Jun. 17, 2003.

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