, 2003), or downregulation of GABA, GAD, or pre- and postsynaptic GABA receptors (Castro-Lopes et al., 1993, Eaton et al., 1998, Fukuoka et al., 1998, Ibuki et al., 1997 and Polgár et al., 2004). Not surprisingly, many pharmacological approaches to managing nerve injury-induced
neuropathic pain enhance inhibitory controls. Ixazomib manufacturer Indeed, significant analgesia can be achieved by activating spinal GABAA or GABAB receptors in various models of inflammatory and neuropathic pain (Asiedu et al., 2010, Knabl et al., 2008 and Munro et al., 2009). The pharmacological regulation of GABA controls, however, is not straightforward. For example, some patients do not respond to these therapies and adverse side effects, which result from systemic drug administration, are dose limiting. Here, we describe a potentially disease-modifying therapeutic
approach designed to restore the inhibitory tone in the spinal cord. This approach consists of transplanting embryonic GABAergic neuronal precursors in the dorsal horn of the spinal cord. Previous studies reported that embryonic GABAergic cortical interneuron precursors from the medial ganglionic eminence (MGE) grafted into adult forebrain EPZ-6438 ic50 disperse and synaptically integrate into functional circuits (Baraban et al., 2009, Southwell et al., 2010 and Wichterle et al., 1999). These grafts are effective in different neurological disorders associated with neuronal hyperexcitability, for example, animal models of epilepsy (Alvarez-Dolado et al., 2006, Baraban et al., 2009, Calcagnotto et al., 2010 and Martínez-Cerdeño et al., 2010). Here, we asked whether MGE transplants
are also viable in the spinal cord, which is outside of their natural environment. We then investigated whether MGE cells can receive and form connections within local circuits of the host dorsal horn. Finally, we assessed the behavioral consequences of transplanting MGE cells in mouse models of inflammatory and nerve injury-induced pain. We report that MGE cells survive outside of the forebrain, retain features of cortical interneurons, integrate into host spinal cord circuitry, and promote an almost else complete reversal of the mechanical hypersensitivity generated by the nerve but not tissue injury. We first asked whether the spinal cord environment was sufficient to promote survival of the MGE cells transplants. To this end, we used MGE cells that express green fluorescent protein (GFP) under the control of the Gad1 (GAD67) promoter ( Tamamaki et al., 2003). In these mice, GAD+/GABAergic MGE cells constitutively express GFP. Figures 1A–1B illustrate expression of GFP in the spinal cord of naive, noninjured adult mice, 1 day after transplantation of MGE cells into the dorsal horn. Most transplanted GFP+ cells formed an aggregate at or near the injection site, with some cells dispersed along the needle track. Isolated cells were occasionally detected at a distance from the heart of the injection site.
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