Interneuron Transplantation as a Treatment for Epilepsy

Hunt, Reid; Baraban, Scott C.

doi:10.1101/cshperspect.a022376

Cited by 53 publications

(44 citation statements)

References 99 publications

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“…1 D ). These results using ChR2 mouse donor embryos are consistent with previous studies (Alvarez-Dolado et al, 2006; Baraban et al, 2009; Southwell et al, 2012; Hunt et al, 2013; Howard et al, 2014; Sebe et al, 2014a, 2014b; Hunt and Baraban, 2015; Howard and Baraban, 2016)…”

Section: Resultssupporting

confidence: 93%

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

Hsieh

Baraban

2017

eNeuro

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Medial ganglionic eminence (MGE) transplantation rescues disease phenotypes in various preclinical models with interneuron deficiency or dysfunction, including epilepsy. While underlying mechanism(s) remains unclear to date, a simple explanation is that appropriate synaptic integration of MGE-derived interneurons elevates GABA-mediated inhibition and modifies the firing activity of excitatory neurons in the host brain. However, given the complexity of interneurons and potential for transplant-derived interneurons to integrate or alter the host network in unexpected ways, it remains unexplored whether synaptic connections formed by transplant-derived interneurons safely mirror those associated with endogenous interneurons. Here, we combined optogenetics, interneuron-specific Cre driver mouse lines, and electrophysiology to study synaptic integration of MGE progenitors. We demonstrated that MGE-derived interneurons, when transplanted into the hippocampus of neonatal mice, migrate in the host brain, differentiate to mature inhibitory interneurons, and form appropriate synaptic connections with native pyramidal neurons. Endogenous and transplant-derived MGE progenitors preferentially formed inhibitory synaptic connections onto pyramidal neurons but not endogenous interneurons. These findings demonstrate that transplanted MGE progenitors functionally integrate into the postnatal hippocampal network.

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Section: Resultssupporting

confidence: 93%

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

Hsieh

Baraban

2017

eNeuro

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“…CGE progenitors transplanted into adult mouse hippocampus also migrate and integrate as GABAergic neurons 12,13 . In contrast to MGE, CGE transplanted progenitors primarily differentiate to calretinin, vasoactive intestinal protein (VIP) and reelin-positive interneuron sub-populations shown to form functional synapses with excitatory and inhibitory neurons.…”

Section: Resultsmentioning

confidence: 99%

“…Because interneurons derived from the CGE can migrate and integrate when transplanted in the neonatal or adult brain 12,13,48 , we also tested whether CGE progenitors could be beneficial for epilepsy therapy. As small numbers of migrating MGE progenitors can contaminate anatomical CGE transplants 48 we used a genetic manipulation to ablate Nkx2.1 + MGE progenitor cells from our CGE transplants 13 .…”

Section: Discussionmentioning

confidence: 99%

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Casalia

Howard

Baraban

2017

Annals of Neurology

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Objective A significant proportion of the more than 50 million people world-wide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities. Methods Transplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post hoc immunohistochemistry was used to confirm cell identity. Results MGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84–88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naïve levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intra-hippocampal CGE progenitors. Interpretation Our findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency and rescue behavioral deficits in a chronic epileptic animal model more than six months after treatment.

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“…As the CGE is a caudal extension of both LGE and MGE, using the most rostral aspect of the CGE for transplantation may give rise to grafts enriched in LGE-derived cells that exhibit poor dispersal (Wichterle et al, 1999). However, in line with genetic fate mapping studies (Miyoshi et al, 2010; Rudy et al, 2011), CGE transplant-derived interneurons were more likely to localize to cortical layer I (Larimer et al, 2016) and express VIP, CR, and RLN (Hunt and Baraban, 2015; Isstas et al, 2016; Larimer et al, 2016) (Fig. 2).…”

Section: Transplantation and The Study Of Brain Developmentmentioning

confidence: 52%

“…1). Not surprisingly, CGE transplant-derived cells were found to migrate extensively following heterochronic transplantation in the neonatal brain, with a dispersal similar to that of MGE cells (Hunt and Baraban, 2015; Larimer et al, 2016), thus suggesting that tangential migration of ventral forebrain inter-neuron precursors is a determinant factor for their dispersal upon transplantation. However, conflicting results were found following transplantation in the adult brain, with one report describing the failure of CGE cells to disperse in the mature cortex (Davis et al, 2015) and another study showing accentuated dispersal of CGE cells compared to that of MGE cells (Isstas et al, 2016).…”

Section: Transplantation and The Study Of Brain Developmentmentioning

confidence: 95%

Transplantation of GABAergic interneurons for cell-based therapy

Spatazza

Leon

Alvarez-Buylla

2017

Functional Neural Transplantation IV - Translation to Clinical Application, Part B

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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.

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Interneuron Transplantation as a Treatment for Epilepsy

Cited by 53 publications

References 99 publications

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

Persistent seizure control in epileptic mice transplanted with gamma‐aminobutyric acid progenitors

Transplantation of GABAergic interneurons for cell-based therapy

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