Forebrain GABAergic Neuron Precursors Integrate into Adult Spinal Cord and Reduce Injury-Induced Neuropathic Pain

Abstract

Neuropathic pain is a chronic debilitating disease characterized by mechanical allodynia and spontaneous pain. Because symptoms are often unresponsive to conventional methods of pain treatment, new therapeutic approaches are essential. Here, we describe a strategy that not only ameliorates symptoms of neuropathic pain, but is also potentially disease modifying. We show that transplantation of immature telencephalic GABAergic interneurons from the mouse medial ganglionic eminence (MGE) into the adult mouse spinal cord completely reverses the mechanical hypersensitivity produced by peripheral nerve injury. Underlying this improvement is a remarkable integration of the MGE transplants into the host spinal cord circuitry, in which the transplanted cells make functional connections with both primary afferent and spinal cord neurons. By contrast, MGE transplants were not effective against inflammatory pain. Our findings suggest that MGE-derived GABAergic interneurons overcome the spinal cord hyperexcitability that is a hallmark of nerve-injury induced neuropathic pain.

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

“…However, the basic culture conditions for growing neurons in vitro have not been updated to reflect fundamental principles of brain physiology. Currently, most human neuronal cultures are grown in media based on DMEM/F12 (4,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), Neurobasal (25)(26)(27)(28)(29)(30), or a mixture of DMEM and Neurobasal (DN) (31)(32)(33)(34). To promote neuronal differentiation and survival, a variety of supplements, such as serum, growth factors, hormones, proteins, and antioxidants, are typically added to these basal media.…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…While the precise mechanisms underlying this state are still being explored, it is believed that impairments in spinal cord dorsal horn inhibitory circuits, including the loss of GABAergic interneurons, is one of the major reasons for persistent neuropathic pain following nerve injury (Braz et al, 2012). In the spinal cord, local interneurons and descending inhibitory circuits modulate pain sensations that are processed in the superficial layers of the dorsal horn.…”

“…Overall, this study showed the beneficial effects of GABA-ergic NPC grafting in attenuating neuropathic pain resulting from peripheral nerve injury. Another study examined the effects of grafting of GABA-ergic progenitors from E12.5-13.5 mouse MGE into the lumbar spinal cord segments of mice displaying neuropathic pain following spared sciatic nerve injury (Braz et al, 2012, Table 2), which was accomplished through transection of two of the three terminal branches of the sciatic nerve. This study showed that GABA-ergic cell grafting reversed mechanical hypersensitivity but not inflammatory pain.…”

“…Author manuscript; available in PMC 2017 May 01. adult brain than lateral ganglionic eminence (LGE, a major source of olfactory bulb interneurons) progenitors that mostly remain in clusters at injection sites (Wichterle et al, 1999(Wichterle et al, , 2001Hattiangady et al, 2008;Southwell et al, 2014). Furthermore, MGE progenitors seem to produce the complement of interneuron subtypes normally produced by them during development even when grafted into the adult cerebral cortex, hippocampus or the spinal cord (Alvarez-Dolado et al, 2006;Wichterle et al, 1999;Southwell et al, 2010Southwell et al, , 2014Braz et al, 2012;Hvou fu am., 2013).…”

Stem cell therapies for neuropathic pain

“…Evidence in support of this used mouse ES cell-derived MGE cortical inhibitory precursor cells, which were transplanted into a mouse model of peripheral sciatic nerve injury. 23 Using ES cell-derived MGE cells that expressed GFP under the control of the Gad1 promoter, it was demonstrated that the ES cell-derived MGE grafts adapted and thrived in the novel spinal cord environment and migrated throughout the ipsilateral dorsal and ventral horns. Within two weeks of transplantation the grafted cells showed immunocytochemical evidence of differentiation towards a neuronal phenotype (NeuN+) and likewise demonstrated immunoreactivity for markers of cortical GABAergic interneurons, namely GABA, neuropeptide Y, parvalbumin and somatostatin.…”