Transplanted adult neural progenitor cells survive, differentiate and reduce motor function impairment in a rodent model of Huntington's disease Elena M. Vazey, Kevin Chen, Stephanie M. Hughes, Bronwen Connor ⁎ Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand Received 8 June 2005; revised 12 December 2005; accepted 5 January 2006 Available online 19 April 2006 Abstract The present study investigated the ability for adult rat neural progenitor cells to survive transplantation, structurally repopulate the striatum and improve motor function in the quinolinic acid (QA) lesion rat model of Huntington's disease. Neural progenitor cells were isolated from the subventricular zone of adult Wistar rats, propagated in culture and labeled with BrdU (50 μM). Fourteen days following QA lesioning, one group of rats (n = 12) received a unilateral injection of adult neural progenitor cells (∼180,000 cells total) in the lesioned striatum, while a second group of rats (n = 10) received a unilateral injection of vehicle only (sham transplant). At the time of transplantation adult neural progenitor cells were phenotypically immature, as demonstrated by SOX2 immunocytochemistry. Eight weeks following transplantation, ∼12% of BrdU-labeled cells had survived and migrated extensively throughout the lesioned striatum. Double-label immunocytochemical analysis demonstrated that transplanted BrdU-labeled progenitor cells differentiated into either astrocytes, as visualized by GFAP immunocytochemistry, or mature neurons, demonstrated with NeuN. A proportion of BrdU-labeled cells also expressed DARPP-32 and GAD 67 , specific markers for striatal medium spiny projection neurons and interneurons. Rats transplanted with adult neural progenitor cells also demonstrated a significant reduction in motor function impairment as determined by apomorphine-induced rotational asymmetry and spontaneous exploratory forelimb use when compared to sham transplanted animals. These results demonstrate that adult neural progenitor cells survive transplantation, undergo neuronal differentiation with a proportion of newly generated cells expressing markers characteristic of striatal neurons and reduce functional impairment in the QA lesion model of Huntington's disease. © 2006 Elsevier Inc. All rights reserved. Keywords: Huntington's disease; Quinolinic acid lesion model; Adult neural progenitor cells; Subventricular zone; Adult brain; Transplantation Introduction Huntington's disease is an autosomal dominant genetic disorder caused by an expansion mutation of a naturally occurring trinucleotide (CAG) repeat in exon 1 of the IT15 gene, encoding a 350-kDa protein termed huntingtin (Hunting- ton's Disease Collaborative Research Group, 1993). This mutation results in excessive involuntary movements (chorea) accompanied by cognitive deficits and behavioural changes due to the progressive and selective degeneration of striatal GABAergic medium spiny projection neurons. At present, there is no clinical treatment to prevent or reduce the onset or progression of Huntington's disease. Cell transplantation therapy may offer a viable treatment strategy for patients with Huntington's disease. Indeed, there is much evidence from animal studies showing that neuronal replacement and partial reconstruction of neuronal circuitry is possible following cell transplantation (Lindvall, 1995; Gage, 1998; Bjorklund and Lindvall, 2000; Nakao and Itakura, 2000). In particular, cell transplantation therapy appears to be well justified for patients with Huntington's disease and previous studies have demon- strated the functional efficacy of transplanting developing striatal neurons in several rodent and primate models of Huntington's disease (Wictorin, 1992; Bjorklund et al., 1994; Dunnett, 1995; Kendall et al., 1998; Palfi et al., 1998). This has lead to the commencement of clinical trials in several centers for cell transplantation therapy for Huntington's disease using intrastriatal implantation of human fetal striatal tissue (Philpott et al., 1997; Kopyov et al., 1998; Rosser and Dunnett, 2003). Experimental Neurology 199 (2006) 384 – 396 www.elsevier.com/locate/yexnr ⁎ Corresponding author. Fax: +64 9 373 7556. E-mail address: b.connor@auckland.ac.nz (B. Connor). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.01.034