hPSC-Derived Maturing GABAergic Interneurons Ameliorate Seizures and Abnormal Behavior in Epileptic Mice

Abstract

Summary Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human PSC has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that human PSC-derived maturing GABAergic interneurons (mGIN) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness and hyperactivity. These results provide support for the potential of human PSC-derived mGIN for restorative cell therapy for epilepsy.

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…2 illustrates the major steps involved in the generation of GABA-ergic progenitors from hESCs and hiPSCs and the utility of such cells for grafting in conditions such as schizophrenia, PD, AD and neuropathic pain. A few studies have also examined the efficacy of such cells in animal models of disease (Cunningham et al, 2014;Hattiangady et al, 2013). Yet, a faster protocol for generating GABA-ergic progenitors from pluripotent stem cells (PSCs), and strategies that promote quicker differentiation of these cells into GABA-ergic interneurons after grafting are required, as the current protocols require extended periods for conversion of hESCs/hiPSCs into GABA-ergic progenitors and these GABA-ergic progenitors tend to differentiate at a slower pace after grafting (Cunningham et al, 2014).…”

Synaptic integration of transplanted interneuron progenitor cells into native cortical networks

“…Henderson et al 2014;Hunt et al 2014), neuropathic pain (Bráz et al 2012), Alzheimer's disease (Tong et al 2014), and schizophrenia (Perez and Lodge 2013), all of which are associated with network hyperexcitability. Human neural progenitor cells, transplanted into mice, also show the ability to integrate as functional interneurons (Zhou et al 2015) and suppress seizures (Cunningham et al 2014). Although it has been suggested that modulation of inflammation (Southwell et al 2014) may represent an underlying mechanism of action for these therapeutic effects, the congruence of evidence, including our present demonstration that MGE-derived PVϩ neurons receive excitatory synaptic input and make inhibitory synaptic output onto principal cells, supports a conclusion that generation of new and fully functional inhibitory synapses in the host brain is a more plausible explanation.…”

Model systems for studying cellular mechanisms ofSCN1A-related epilepsy

“…In a recent study, human iPSC-derived maturing GABAergic interneurons were injected into the brains of mice with temporal lobe epilepsy (TLE), where they integrated into the host tissue and were capable of inducing inhibitory postsynaptic responses in host hippocampal neurons. Additionally, the transplanted cells suppressed seizures and behavioral abnormalities in TLE mice (Cunningham et al 2014). Although there is still a long way to go before iPSC-derived neurons can be used to treat patients, these early findings show promise in developing new therapeutics for patients with refractory epilepsies.…”