GABAergic Neuronal Precursor Grafting: Implications in Brain Regeneration and Plasticity

Hindawi Publishing Corporation Neural Plasticity Volume 2011, Article ID 384216, 11 pages doi:10.1155/2011/384216 Review Article GABAergic Neuronal Precursor Grafting: Implications in Brain Regeneration and Plasticity Manuel Alvarez Dolado1 and Vania Broccoli2 1 Department of Cell Therapy and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), 41092 Seville, Spain 2 Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy Correspondence should be addressed to Manuel Alvarez Dolado, and Vania Broccoli, Received 23 February 2011; Accepted 11 April 2011 Academic Editor: Graziella Di Cristo Copyright © 2011 M. Alvarez Dolado and V. Broccoli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Numerous neurological disorders are caused by a dysfunction of the GABAergic system that impairs or either stimulates its inhibitory action over its neuronal targets. Pharmacological drugs have generally been proved very effective in restoring its normal function, but their lack of any sort of spatial or cell type specificity has created some limitations in their use. In the last decades, cell-based therapies using GABAergic neuronal grafts have emerged as a promising treatment, since they may restore the lost equilibrium by cellular replacement of the missing/altered inhibitory neurons or modulating the hyperactive excitatory system. In particular, the discovery that embryonic ganglionic eminence-derived GABAergic precursors are able to disperse and integrate in large areas of the host tissue after grafting has provided a strong rationale for exploiting their use for the treatment of diseased brains. GABAergic neuronal transplantation not only is efficacious to restore normal GABAergic activities but can also trigger or sustain high neuronal plasticity by promoting the general reorganization of local neuronal circuits adding new synaptic connections. These results cast new light on dynamics and plasticity of adult neuronal assemblies and their associated functions disclosing new therapeutic opportunities for the near future. 1. Introduction γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS), playing a key role in the balance between inhibitory and excitatory circuits [1, 2]. Therefore, it is not surprising that dysfunctions in the GABAergic system lead to pathological conditions including hypokinetic diseases such as Parkinson’s disease (PD), and hyperkinetic diseases, such as Huntington’s disease (HD), when disruption of the GABAergic system occurs in the basal ganglia [3–5]. Epilepsy, a pathology characterized by uncontrolled hyperactivity, is also tightly linked to deficits in GABA levels, as well as alterations in its synthesis, secretion, and reuptake, or reductions in the number of GABAergic interneurons [6–8]. Almost 25 years ago, it was already postulated that controlling GABA delivery to specific brain areas should benefit each of these diseases [9, 10]. Cell transplantation is a powerful tool to introduce a new source of GABA and may allow reconstitution of neural circuits in the diseased brain [11, 12]. To be successful, grafted cells should possess the ability to disperse through affected areas and differentiate into fully mature neurons expressing appropriate neurotransmitters, in this case GABA. Ideally, these cells should also functionally integrate and modulate circuitry activity in the damaged host brain; for instance, affecting its plasticity. Since the pioneer works from Lindvall and Björklund [9] and Isacson et al. [10], several transplantation assays with different GABA-producing cell types have been performed with disparate success in animal models of diseases. Many cell types were partially successful in reverting some of the pathological anomalies observed in the grafted models. However, some of them presented important drawbacks, such as their poor tissue distribution, transient effect, maybe 2 due to decreased GABA release over time [13–15], or in the case of ES cells, the lack of safety due to potential generation of teratocarcinomas [16, 17]. In the last decade, a better comprehension of how and where the cortical and hippocampal interneurons originate has led to use their neuronal precursors in transplantation [18, 19]. We currently know that most of the GABAergic interneurons in the cortex and hippocampus are mainly generated in two regions of the subcortical telencephalon, known as the caudal and medial ganglionic eminence (CGE and MGE), from where they migrate tangentially to their final destination in the cerebral cortex [19–22]. In the last years, several groups have reported regenerative works using these MGE-derived GABAergic precursors, with striking results [23–28]. At present, they represent the most promising cell-based therapeutic alternative for GABArelated diseases. In this paper, we will summarize the main regenerative approaches using GABAergic grafts for the treatment of epilepsy and neurodegenerative disorders. These include the use of different sources of GABAergic precursors, with a special emphasis in the MGE-derived cells, and their transplant in several model organisms of disease. In addition, we will also describe the implications of the GABAergic grafts on the modulation of synaptic activity and circuitry plasticity of the host. 2. GABAergic Cell Therapy for Epilepsy Epileptic seizures reflect a hyperexcitation in the brain, which is attributed to an imbalance between inhibitory and excitatory networks [6]. Given the close relationship between GABA and epilepsy [6, 8], antiepileptic drugs (AED) targeting the GABAergic system are traditionally the preferred treatment, presenting an acceptable efficacy [29, 30]. However, up to a third of patients continue to experience seizures on maximal tolerated drug therapy [31, 32]. Refractory epilepsy remains a large clinical problem, since surgical resection is only appropriate for a minority of patients [33, 34]. In the last decades, cell-based therapies using GABAergic grafts have emerged as an alternative treatment for epilepsy, since they may restore the lost equilibrium by cellular replacement of the missing/altered inhibitory neurons or modulating the hyperactive excitatory system [35–37]. The therapeutic strategies are multiple: general secretion of GABA, by the grafted cells to increase the seizure threshold, or specifically located in the focus of epilepsy and/or the areas responsible for seizure transmission to block it; direct replacement of malfunctioning or lost inhibitory interneurons; interaction of the transplanted GABAergic cells with activating system to modulate its plasticity, and levels of activity; finally, rewiring of aberrant excitatory fibers, such as mos (...truncated)