Grafting of GABAergic precursors rescues deficits in hippocampal inhibition * 1 Maria E. Calcagnotto, *y 1 Ivan Zipancic, *Marina Piquer-Gil, zLuiz E. Mello, and *Manuel A ´ lvarez-Dolado *Department of Cell Therapy and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville, Spain; yCentro de Investigacio ´ n Prı ´ncipe Felipe (CIPF), Valencia, Spain; and zDepartment of Physiology, Universidade Federal de Sa ˜ o Paulo (UNIFESP), Sa ˜ o Paulo, Brazil SUMMARY c-Aminobutyric acid (GABA) has an important role in the mechanism of epilepsy. Cell grafts from different sources have been performed to modu- late local circuits or increase GABAergic inhibi- tion in animal models of epilepsy. Among the different transplanted cell types, the medial gan- glionic eminence (MGE)–derived cells present the best properties to be used in cell-based therapy. In this work we review previous experiences with these cells. In addition, we present new evidence showing their ability to modulate the levels of inhi- bition in the host brain of mice with alterations in the GABAergic system, caused by the specific ablation of hippocampal interneurons. Grafted GFP + MGE–derived cells occupied the area of abla- tion and differentiated into mature NK-1-, SOM-, PV-, CR-, and NPY-expressing interneurons. Inhib- itory postsynaptic current (IPSC) frequency and amplitude on CA1 pyramidal cells of the ablated hippocampus significantly increased after trans- plantation, reaching levels similar to controls. Our data strongly suggest the suitability of MGE- derived cells for the treatment of neurologic conditions for which an increase or modulation of synaptic inhibition is required. KEY WORDS: Transplantation, Interneuron, MGE, Cell therapy, Saporin. Epileptogenicity in humans and in animal models of epilepsy is attributed to an imbalance of inhibitory and excitatory networks in the brain (Prince et al., 1997) Anti- convulsant medication is traditionally the main treatment for epilepsy. However, in recent years, cell-based thera- pies have emerged as a new way to modulate local circuit hyperactivity or to increase inhibitory activity (Raedt et al., 2007; Baraban et al., 2009; Kriegstein & Pitkanen, 2009; Thompson, 2009). Given the implication of the c-aminobutyric acid (GABA)ergic system in epilepsy (Prince et al., 1997; Treiman, 2001), different sources of GABAergic cells have been assayed as cell replacement therapy in epilepsy (Stevens et al., 1988; Fine et al., 1990; Loscher et al., 1998; Alvarez-Dolado et al., 2006; Raedt et al., 2007; Baraban et al., 2009; Thompson, 2009). Fetal precursors or cells genetically modified to produce and secrete GABA have been transplanted into the hippocam- pus or in regions implicated in seizure generalization (Loscher et al., 1998; Eaton et al., 1999; Thompson & Suchomelova, 2004; Hattiangady et al., 2008; Baraban et al., 2009; Thompson, 2009). The origin of these cortical and hippocampal GABAergic interneurons is mainly located in two regions of the subcortical telencephalon, known as the caudal and medial ganglionic eminence (MGE), from where they migrate tangentially to their final destination (Marin & Rubenstein, 2001; Wichterle et al., 2001; Xu et al., 2004).This review addresses experimen- tation using MGE-derived precursors as a source of GABAergic neurons to modulate the levels of inhibition in the host brain under neuropathologic conditions. Herein we include our results of MGE grafts in mice with specific alterations in the GABAergic system. Address correspondence to Manuel lvarez-Dolado, Centro de Bio- logía Molecular y Medicina Regenerativa (CABIMER), Av. Americo Vespucio s/n – Seville 41092, Spain. E-mail: manuel.alvarez@cabimer.es 1 These authors contributed equally to this work. Wiley Periodicals, Inc. ª 2010 International League Against Epilepsy Epilepsia, 51(Suppl. 3): 66–70, 2010 doi: 10.1111/j.1528-1167.2010.02613.x NOVEL THERAPEUTIC TARGETS AND APPROACHES 66