Understanding Epilepsy Using iPSC-Derived Neurons

Epilepsy is a common neurological disorder that typically has an early age of onset and the potential for serious neurocognitive residuals in later life [1]. Symptoms may include seizures, recurring aggressive electrical activity, and neurological, cognitive and behavioral difficulties with the condition sometimes causing early death [2].

Epilepsy Neural Stem Cells (ax0411) cultured on Sure Bond+ (ax0041+). Image taken after 3 days of spontaneous differentiation in Neural Expansion-XF Medium (ax0030-500). nestin (R) - FOXG1 (G)

Epilepsy Neural Stem Cells (ax0411) cultured on Sure Bond+ (ax0041+). Image taken after 3 days of spontaneous differentiation in Neural Expansion-XF Medium (ax0030-500). nestin (R) - FOXG1 (G)

In at least 70% of patients, genetic factors are thought to play a role [1]. An example of genetic influence is the SLC25A22 gene which codes for a mitochondrial glutamate transporter. This gene is associated with early-onset epileptic encephalopathies (OMIM #609304), for example early myoclonic encephalopathy, and several mutations in this gene have already been identified in epilepsy patients (rs121918334, rs121918335, rs587777243).

For individuals with epilepsy, the prognosis can be poor [3]. Therefore, a model system is required in order to determine the effects of epilepsy-associated mutations like these on human neurons as well as to help identify more effective treatments.

Human Cells are Required for Effect Disease Modeling and Drug Discovery

Understanding development, memory and learning in brain function has, for many years, relied heavily upon the use of animal models. Although animal models have elucidated some mechanisms in brain function, a human model is required in order to validate and further evaluate these findings.

Obtaining a human model can often be challenging. However, human induced pluripotent stem cells (hiPSCs) can be differentiated into neural cells and used to study electrical conductivity and network formation in vitro [4]. These lines can be derived from a single donor and made available on an industrial scale.

This produces an isogenic source of cells from one individual which provides consistency throughout the experimental process. Moreover, it is possible to derive these cell lines from both patient donors and healthy individuals which has led to an increase in the uptake of these cells in drug discovery as well as helping to improve understanding of the disease mechanisms that underpin conditions like epilepsy and neurodegenerative conditions (for example Parkinson’s, Alzheimer’s and Huntington’s diseases).

Using Human Induced Pluripotent Stem Cells to Study Epileptiform Phenomena

Human iPSC-derived neurons have the potential to be powerful in vitro models for evaluating drug responses and disease mechanisms. In a paper by Odawara et al. (2015), astrocytes were co-cultured with Axol’s Human iPSC-Derived Cerebral Cortical Neurons for over 100 days on a multi-electrode array (MEA), with the aim of studying plasticity such as long-term potentiation depression (LTD) and long-term potentiation (LTP) in neuronal networks. The cells were then maintained for 400 days and the pharmacological responses and spontaneous electrical activity in cultured human iPSC-derived cortical neurons using MEA were investigated.

Several pharmacological studies were conducted in order to determine the properties of evoked responses upon administration of synapse antagonists CNQX, AP5 and bicuculine and the agonist, L-glutamate, a kainic acid. This induced significant changes in synchronized burst firing activity and firing rates. Epileptiform activity was also induced in these cells using pentylentetrazole (PTZ), and the suppressive effects of clinical anti-epilepsy drugs, like phenytoin, were observed at a variety of concentrations over several weeks.

Future Potential for Human iPSC-Derived Neural Cells in Epilepsy Research

Further work is needed in order to standardize cell culture protocols for these cells and to establish functional evaluation methods. The cells used in this example are derived from a healthy individual, but iPSCs derived from patient donors are essential for future studies. This will enable the comparison across disease-relevant genetic backgrounds and controls.

Human iPSC-derived neural cells have great potential to clarify human neuronal network function and further the understanding of new biological pathways. These systems could be used to model disease and help identify the mechanisms underpinning alternate firing patterns in conditions like epilepsy. Since they provide a relevant cell type for the investigation of novel compounds for the effective treatment of these conditions, these cells are also important for applications such as drug screening.

References

[1] Hildebrand MS, et al., Recent advances in the molecular genetics of epilepsy. J. Med. Genet. 50:271-279, 2013.

[2] Epilepsy Foundation. Epileptic Encephalopathies in Infancy and Childhood. http://www.epilepsy.com/information/professionals/about-epilepsy-seizures/epileptic-encephalopathies-infancy-and-childhood

[3] Molinari, F, et al., Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am. J. Hum. Genet. 76: 334-339, 2005

[4] Odawara A, et al., Induction of long-term potentiation and depression phenomena in human induced pluripotent stem cell-derived cortical neurons. Biochemical and Biophysical Research Communications, 2015

About AXOL Biosciences

Axol specializes in human cell culture.

Axol produces high quality human cell products and critical reagents such as media and growth supplements. We have a passion for great science, delivering epic support and innovating future products to help our customers advance faster in their research.

Our expertise includes reprogramming cells to iPSCs and then differentiating to various cell types. We supply differentiated cells derived from healthy donors and patients of specific disease backgrounds. As a service, we also take cells provided by customers (primary or iPSC) and then do the reprogramming (when necessary) and differentiation. Clearly, by offloading the burden of generating cells, your time is freed up to focus on the research. Axol holds the necessary licenses that are required to do iPSC work.

The package wouldn't be complete without optimized media, coating solutions and other reagents. Our in-house R&D team works hard to improve on existing media and reagents as well as innovate new products for human cell culture. We also supply a growing range of human primary cells; making Axol your first port of call for your human cell culture needs.


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Last updated: Sep 30, 2019 at 11:06 AM

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