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. 2017;231:57-85.
doi: 10.1016/bs.pbr.2016.11.005. Epub 2017 Mar 17.

Transplantation of GABAergic Interneurons for Cell-Based Therapy

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Free PMC article

Transplantation of GABAergic Interneurons for Cell-Based Therapy

Julien Spatazza et al. Prog Brain Res. .
Free PMC article

Abstract

Many neurological disorders stem from defects in or the loss of specific neurons. Neuron transplantation has tremendous clinical potential for central nervous system therapy as it may allow for the targeted replacement of those cells that are lost in diseases. Normally, most neurons are added during restricted periods of embryonic and fetal development. The permissive milieu of the developing brain promotes neuronal migration, neuronal differentiation, and synaptogenesis. Once this active period of neurogenesis ends, the chemical and physical environment of the brain changes dramatically. The brain parenchyma becomes highly packed with neuronal and glial processes, extracellular matrix, myelin, and synapses. The migration of grafted cells to allow them to home into target regions and become functionally integrated is a key challenge to neuronal transplantation. Interestingly, transplanted young telencephalic inhibitory interneurons are able to migrate, differentiate, and integrate widely throughout the postnatal brain. These grafted interneurons can also functionally modify local circuit activity. These features have facilitated the use of interneuron transplantation to study fundamental neurodevelopmental processes including cell migration, cell specification, and programmed neuronal cell death. Additionally, these cells provide a unique opportunity to develop interneuron-based strategies for the treatment of diseases linked to interneuron dysfunction and neurological disorders associated to circuit hyperexcitability.

Keywords: Epilepsy; Ganglionic eminence; Interneuron; Plasticity; Transplantation.

Figures

FIG. 1:
FIG. 1:
Heterochronic transplantation of interneuron progenitors. The MGE or CGE is dissected from the embryonic mouse brain. The MGE is anatomically separated from the LGE by a large sulcus; the CGE is a caudal extension of both LGE and MGE. Dissociated cells from these ganglionic eminences can be transplanted using beveled glass needles into both neonatal and adult nervous system (see text). MGE and CGE interneuron progenitors have the ability to migrate and differentiate into multiple interneuron subtypes that become integrated into functional circuits; dispersal is more robust in the permissive neonatal brain.
FIG. 2:
FIG. 2:
Transplant-derived interneuron development in the heterochronic environment. MGE and CGE progenitors were transplanted into the cortex of a P2 host. At 6 days posttransplantation (6DAT), many MGE and CGE transplant-derived cells are found within the superficial layers of the cortex and are tangentially oriented, a behavior reminiscent of endogenous interneuron migration within the marginal zone of the developing neocortex (top). A large number of cells have also started to invade the cortex at 6DAT and display a radial orientation (top). At this stage, virtually all transplant-derived cells display a typical migratory morphology, with a long leading process and a short trailing process (bottom). At 20DAT, many transplanted interneurons have undergone programmed cell death. The transplanted MGE cells that survive usually stay clear of cortical layer I (as opposed to transplanted CGE cells), distribute across all cortical layers (top), and display a more mature morphology (bottom). At 35DAT, the vast majority of MGE transplant-derived cells differentiate into GABAergic interneurons expressing either PV or SST. CGE transplants give rise to many neurogliaform neurons that express RLN and to VIP-expressing interneurons. Neurogliaform interneurons mostly localize to layer I. CC, corpus callosum. Scale bar: 50 μm.
FIG. 3:
FIG. 3:
Immature interneuron transplantation and therapeutic applications. (Top) Immature interneurons can be obtained directly from the embryonic MGE or in vitro from embryonic stem (ES) or induced pluripotent stem (IPS) cells directed to differentiate into MGE-like progenitors. Interneurons have been transplanted into multiple regions of the CNS, including the striatum, neocortex, hippocampus, and spinal cord. Transplanted interneurons display disease-modifying activity in animal models of Parkinson’s disease, Alzheimer’s disease, epilepsy, schizophrenia, anxiety, spasticity, chronic pain, and neuropathic itch. (Bottom) Interneuron transplantation has also been used to study and manipulate cortical plasticity. The timing of native critical period of plasticity in the mouse visual cortex is dictated by the maturation of endogenous interneurons. Ocular dominance plasticity peaks at around P30 when inhibitory neurons are approximately 35 days of age (35D). Upon transplantation into both neonatal and adult visual cortex, interneurons induce ocular dominance plasticity when they reach a similar cellular age at approximately 35 days after transplantation (35DAT). Transplant-induced plasticity allows functional recovery of visual acuity in mouse models of developmentally acquired amblyopia. These findings suggest that interneuron development is governed by molecular programs established in the embryo and that these programs are retained and executed by embryonic interneurons upon heterochronic transplantation.

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