Changes in function and ultrastructure of striatal dopaminergic terminals that regenerate following partial lesions of the SNpc

Authors


Address correspondence and reprint requests to Professor Malcolm K. Horne, Howard Florey Institute of Experimental Physiology and Medicine, The University of Melbourne Victoria, 3010, Australia. E-mail: m.horne@hfi.unimelb.edu.au

Abstract

Following partial substantia nigra lesions, remaining dopaminergic neurones sprout, returning terminal density in the dorsal striatum to normal by 16 weeks. This suggests regeneration and maintenance of terminal density is regulated to release appropriate levels of dopamine. This study examined the structure and function of these reinnervated terminals, defining characteristics of dopamine uptake and release, density and affinity of the dopamine transporter (DAT) and ultrastructural morphology of dopamine terminals in the reinnervated dorsal striatum. Finally, rotational behaviour of animals in response to amphetamine was examined 4 and 16 weeks after substantia nigra pars compacta (SNpc) lesions. Dopamine transport was markedly reduced 16 weeks after lesioning along with reduced density and affinity of DAT. Rate of dopamine release and peak concentration, measured electrochemically, was similar in lesioned and control animals, while clearance was prolonged after lesioning. Ultrastructurally, terminals after lesioning were morphologically distinct, having increased bouton size, vesicle number and mitochondria, and more proximal contacts on post-synaptic cells. After 4 weeks, tendency to rotate in response to amphetamine was proportional to lesion size. By 16 weeks, rotational behaviour returned to near normal in animals where lesions were less than 70%, although some animals demonstrated unusual rotational patterns at the beginning and end of the amphetamine effect. Together, these changes indicate that sprouted terminals are well compensated for dopamine release but that transport mechanisms are functionally impaired. We discuss these results in terms of implications for dyskinesia and other behavioural states.

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