Neural transplantation: Restoring complex circuitry in the striatum

Article type: Research Article

Authors: Fricker-Gates, Rosemary A. | Lundberg, Cecilia | Dunnett, Stephen B.

Affiliations: Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, P.O. Box 911, Cardiff, CF10 3US, UK | University of Lund, Wallenberg Neuroscience Center, BMC A11, 221 84 Lund, Sweden

Note: [] Corresponding author. Tel.: +44 29 2087 5188; Fax: +44 29 2087 6749; E-mail: [email protected]

Abstract: During the last 30 years, the promise of neural transplantation as a therapeutic strategy for neurodegenerative disease has been slowly recognised. Across the world, clinical transplants of embryonic primary dopamine neurones have been shown to ameliorate some of the motor deficits in Parkinsons disease (PD) patients, and more recently, systematic clinical trials have been initiated for the replacement of striatal pro-jection neurones lost in Huntington's disease (HD) . Clinical transplantation as a prospective therapy for HD poses a particular set of difficulties. The hallmarks of this neurodegenerative disease include extensive loss of medium spiny long-distance projection neurones of the caudate and putamen, affecting downstream target nuclei, the globus pallidus and substantia nigra, leading to dysregulation of motor control. In addition, extensive loss of cortical neurones that form the afferent systems to the basal ganglia leads to widespread cognitive decline. If transplantation therapy is to succeed in replacing degenerating neurones in HD and reinstating controlled function of complex basal gan-glia circuitry, the new neurones must be able to develop specific long-distance projections that can form accurate and functional connections with neurones in precise target regions. Our ongoing studies are aimed at addressing how we can improve the function of striatal transplants, in particular to optimise the reforma-tion of precise long-distance connections and to re-establish normal motor and cognitive function. In particular, we have investigated optimal requirements for embryonic primary tissue to achieve these aims, and also the potential of other cell sources to provide long-distance projection neurones and reconnect complex circuitry. This review describes current progress of experiments to optimise the reconstruction of neu-ronal circuitry using primary embryonic tissue transplants, as well as our current initiatives to use neural stem cells or precursors to replace long distance projection neurones in the degenerating basal ganglia.

Keywords: transplantation, neuronal differentiation, behaviour, function, connectivity, Huntingtons Disease, striatum, neural progenitors

Journal: Restorative Neurology and Neuroscience, vol. 19, no. 1-2, pp. 119-138, 2001