Pluripotent stem cell-derived interneuron progenitors mature and restore memory deficits but do not suppress seizures in the epileptic mouse brain

Anderson, Nickesha C.; Zandt, Meghan A. Van; Shrestha, Swechhya; Lawrence, Daniel Burton; Gupta, Jyoti; Chen, Christopher Y.; Harrsch, Felicia A.; Boyi, Trinithas; Dundes, Carolyn E.; Aaron, Gloster B.; Naegele, Janice R.; Grabel, Laura

doi:10.1016/j.scr.2018.10.007

Cited by 17 publications

(32 citation statements)

References 51 publications

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“…Furthermore, many TLE models investigated in therapeutic studies have also been reported to have much lower (1-2 seizures/day) and inconsistent frequency of seizures, or clusters of SRS occurring one or more times a month [84][85][86][87][88][89]. The use of chronic epilepsy models with irregular frequency for SRS may lead to confounding results and interpretation of the therapeutic efficacy of drugs or biologics unless the study employs continuous video-EEG recordings for several months.…”

Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

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Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.

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Section: Discussionmentioning

confidence: 99%

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Upadhya¹,

Kodali²,

Gitaí³

et al. 2019

Aging and disease

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

“…The cell lines used for transplantation were hES3 NKX2.1: GFP (gift from Dr. Stewart A. Anderson and Dr. Andrew Elefanty) and a modified variant of this line designated hES3 NKX2.1: GFP/ubi: mCherry [ 14 ]. The neural induction and interneuron differentiation protocols were as described previously [ 14 , 24 ]. Briefly, the hESCs were differentiated in LDN (BMP antagonist), Sonic hedgehog (SHH) and the SHH agonist Purmorphomine (Pur) for approximately 18 days, then frozen in liquid nitrogen for storage until they were thawed and dissociated for transplantation.…”

Section: Methodsmentioning

confidence: 99%

“…We transplanted hESC-derived interneuron progenitors into multiple sites in the dorsal hippocampus, as described previously [ 14 ]. Briefly, ~6 weeks old NSG mice were anesthetized with isoflurane gas and stereotaxic surgery was performed using a Quintessential Injection System (Stoelting Co.).…”

Section: Methodsmentioning

confidence: 99%

“…We performed confocal microscopy and reconstructed the dendritic arbors with 3-dimensional (3D) computer-based software. Based on firing responses to current injections, five electrophysiological types (Type I-V) of transplanted hESC-derived interneurons were described in our previous study [ 14 ]. In the present study, we extended these analyses by performing hierarchical clustering on the basis of dendritic arbor morphology.…”

Section: Introductionmentioning

confidence: 99%

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Development of electrophysiological and morphological properties of human embryonic stem cell-derived GABAergic interneurons at different times after transplantation into the mouse hippocampus

et al. 2020

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Transplantation of human embryonic stem cell (hESC)-derived neural progenitors is a potential treatment for neurological disorders, but relatively little is known about the time course for human neuron maturation after transplantation and the emergence of morphological and electrophysiological properties. To address this gap, we transplanted hESC-derived human GABAergic interneuron progenitors into the mouse hippocampus, and then characterized their electrophysiological properties and dendritic arborizations after transplantation by means of ex vivo whole-cell patch clamp recording, followed by biocytin staining, confocal imaging and neuron reconstruction software. We asked whether particular electrophysiological and morphological properties showed maturation-dependent changes after transplantation. We also investigated whether the emergence of particular electrophysiological properties were linked to increased complexity of the dendritic arbors. Human neurons were classified into five distinct neuronal types (Type I-V), ranging from immature to mature fast-spiking interneurons. Hierarchical clustering of the dendritic morphology and Sholl analyses suggested four morphologically distinct classes (Class A-D), ranging from simple/immature to highly complex. Incorporating all of our data regardless of neuronal classification, we investigated whether any electrophysiological and morphological features correlated with time post-transplantation. This analysis demonstrated that both dendritic arbors and electrophysiological properties matured after transplantation.

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Hippocampal transplants of fetal GABAergic progenitors regulate adult neurogenesis in mice with temporal lobe epilepsy

Arshad

Oppenheimer

Jeong

et al. 2022

Neurobiology of Disease

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Pluripotent stem cell-derived interneuron progenitors mature and restore memory deficits but do not suppress seizures in the epileptic mouse brain

Cited by 17 publications

References 51 publications

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology

Development of electrophysiological and morphological properties of human embryonic stem cell-derived GABAergic interneurons at different times after transplantation into the mouse hippocampus

Hippocampal transplants of fetal GABAergic progenitors regulate adult neurogenesis in mice with temporal lobe epilepsy

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