Abstract
Epilepsy is a neurological disorder that affects over 65 million people globally. It is characterized by periods of seizure activity of the brain as a result of excitation and inhibition (E/I) imbalance, which is regarded as the core underpinning of epileptic activity. Both gain- and loss-of-function (GOF and LOF) mutations of ion channels, synaptic proteins and signaling molecules along the mechanistic target of rapamycin (mTOR) pathway have been linked to this imbalance. The pathogenesis of epilepsy often has its roots in the early stage of brain development. It remains a major challenge to extrapolate the findings from many animal models carrying these GOF or LOF mutations to the understanding of disease mechanisms in the developing human brain. Recent advent of the human pluripotent stem cells (hPSCs) technology opens up a new avenue to recapitulate patient conditions and to identify druggable molecular targets. In the following review, we discuss the progress, challenges and prospects of employing hPSCs-derived neural cultures to study epilepsy. We propose a tentative working model to conceptualize the possible impact of these GOF and LOF mutations in ion channels and mTOR signaling molecules on the morphological and functional remodeling of intrinsic excitability, synaptic transmission and circuits, ultimately E/I imbalance and behavioral phenotypes in epilepsy.
Highlights
Reviewed by: Karl Daniel Murray, University of California, Davis, United States Eric Levine, University of Connecticut, United States
To conceptualize the findings from both human in vitro system and rodent models in which the roles of the mechanistic target of rapamycin (mTOR) pathway in regulating ion channels and synaptic receptors are established, we propose a hypothetical working model that dysregulation of mTOR signaling may underlie the inability for neurons to adjust the setpoint in their intrinsic excitability and synaptic inputs, both of which converge to an excitation and inhibition (E/I) imbalance in the network, leading to seizure activity (Figure 1)
Previous animal models have provided important insights into epilepsy, but our lack of understanding in species differences limits our comprehension of epileptogenesis in human brains and the development of effective treatments for patients
Summary
Channelopathy accounts for the majority of genetic mutations associated with epilepsy. Frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the inhibitory neurons decreased, indicating that lowered excitability in these neurons likely attenuates inhibitory output onto other cells to elevate E/I ratio Both inhibitory and excitatory neurons derived from patient cells or CRISPR/Cas engineered iPSCs carrying the same patient mutation SCN1A (K1270T) confirmed convergent phenotypes in inhibitory neurons, including decreased action potential frequency, amplitude, and Na+ current density. The heightened frequency may result from the mutation and lead to a broader voltage range for sodium channel openings (Xie et al, 2020) These findings demonstrate the importance of LOF mutations in inhibitory neurons, but do not rule out the possibility of GOF mutations with a different genetic background targeting excitatory neurons as previously reported. The literature has largely focused on SCN1A, cell lines derived from epilepsy patients with SCN2A and SCN8A LOF mutations have been developed for future studies (Tidball et al, 2017)
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