Differentiation and Functional Incorporation of Embryonic Stem Cell-Derived GABAergic Interneurons in the Dentate Gyrus of Mice with Temporal Lobe Epilepsy
| Autor: | Elizabeth Litvina, Gloster B. Aaron, Laura Grabel, Stephanie Tagliatela, Xu Maisano, Janice R. Naegele |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Mossy fiber (hippocampus) Interneuron Neurogenesis Biology Hippocampal formation Article Cell Line Mice Organ Culture Techniques Interneurons medicine Animals Embryonic Stem Cells gamma-Aminobutyric Acid General Neuroscience Dentate gyrus Mice Inbred C57BL Transplantation Disease Models Animal medicine.anatomical_structure Epilepsy Temporal Lobe nervous system Dentate Gyrus biology.protein GABAergic Calretinin Neuroscience Parvalbumin |
| Zdroj: | The Journal of Neuroscience. 32:46-61 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2683-11.2012 |
| Popis: | Cell therapies for neurological disorders require an extensive knowledge of disease-associated neuropathology and procedures for generating neurons for transplantation. In many patients with severe acquired temporal lobe epilepsy (TLE), the dentate gyrus exhibits sclerosis and GABAergic interneuron degeneration. Mounting evidence suggests that therapeutic benefits can be obtained by transplanting fetal GABAergic progenitors into the dentate gyrus in rodents with TLE, but the scarcity of human fetal cells limits applicability in patient populations. By contrast, virtually limitless quantities of neural progenitors can be obtained from embryonic stem (ES) cells. ES cell-based therapies for neurological repair in TLE require evidence that the transplanted neurons integrate functionally and replace cell types that degenerate. To address these issues, we transplanted mouse ES cell-derived neural progenitors (ESNPs) with ventral forebrain identities into the hilus of the dentate gyrus of mice with TLE and evaluated graft differentiation, mossy fiber sprouting, cellular morphology and electrophysiological properties of the transplanted neurons. Additionally we compared electrophysiological properties of the transplanted neurons to endogenous hilar interneurons in mice without TLE. The majority of transplanted ESNPs differentiated into GABAergic interneuron subtypes expressing calcium-binding proteins parvalbumin, calbindin or calretinin. Global suppression of mossy fiber sprouting was not observed, however, ESNP-derived neurons formed dense axonal arborizations in the inner molecular layer and throughout the hilus. Whole-cell hippocampal slice electrophysiological recordings and morphological analyses of the transplanted neurons identified five basic types; most with strong after-hyperpolarizations and smooth or sparsely spiny dendritic morphologies resembling endogenous hippocampal interneurons. Moreover, intracellular recordings of spontaneous excitatory postsynaptic currents indicated that the new cells functionally integrate into epileptic hippocampal circuitry. |
| Databáze: | OpenAIRE |
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