Single Cell Electrophysiological Characterization of Kleefstra Patient-Derived iNeurons

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Neurodevelopmental disorders (NDDs) are a collection of heterogeneous syndromes involving disruption of early neurobiological development, and are often considered to involve defects in cellular physiology and synaptic communication. Kleefstra syndrome (KS) is a NDD within this class, and is associated with haploinsufficiency of Euchromatin Histone Methyltransferase 1 (EHMT1). Animal work has provided a strong foundation for physiological phenotypes in KS, identifying deficits in homeostatic plasticity, hyperexcitability, and decreased network synchronization. Here, we aimed to elaborate on previous findings in a human model for KS, by using iNeurons differentiated from KS patient- and control- derived IPSCs. We compared four patient-derived lines to a control line in terms of single-cell neuronal intrinsic properties, by means of whole cell patch clamp recordings. Moreover, to support reliability of our results, the patient-derived lines as well as different culturing batches were cross-compared. We showed that KS patient-derived lines revealed altered active properties, indicative of different action potential (AP) shape, and to a lesser extent, decreased excitability. Moreover, KS patient-derived lines were largely homogeneous on intrinsic electrophysiological properties, and no alterations over different culturing batches were found. As EHMT1 is an epigenetic regulator, we suggest that the differences in the AP shape may be caused by a dysregulation of membrane ion channel expression, particularly downregulation of voltage-gated potassium (K+) channels, and could be seen as indicative of immaturity. Although highly speculative, we hypothesize that indications of decreased excitability here, could signal that hyperexcitability in KS may result from astrocyte-neuron interplay. Despite finding indications for iNeurons as reflecting a relatively immature model system in the current study as well as in literature, the intrinsic electrophysiological phenotype found here, provides for relevant future directions in the elucidation of pathophysiology in KS.
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