HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns

Vaibhav P Pai,Michael Levin,Valerie Willocq,Bin Ye,Nian-Qing Shi,Alexis Pietak

doi:10.1038/s41467-018-03334-5

Abstract

Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes. Lack of a model explaining spatialized dynamics of bioelectric states has hindered the understanding of the etiology of some birth defects and the development of predictive interventions. Nicotine, a known neuroteratogen, induces serious defects in brain patterning and learning. Our bio-realistic computational model explains nicotine’s effects via the disruption of endogenous bioelectrical gradients and predicts that exogenous HCN2 ion channels would restore the endogenous bioelectric prepatterns necessary for brain patterning. Voltage mapping in vivo confirms these predictions, and exogenous expression of the HCN2 ion channel rescues nicotine-exposed embryos, resulting in normal brain morphology and molecular marker expression, with near-normal learning capacity. By combining molecular embryology, electrophysiology, and computational modeling, we delineate a biophysical mechanism of developmental brain damage and its functional rescue.

Highlights

Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes
The majority of these effects of nicotine occur through its action on nicotinic acetyl choline receptors, but it is not known how this bioelectric change at the single-cell level alters whole organ morphogenesis of the brain
We report the first biorealistic computational model of Xenopus embryos, which predicts that nicotine disrupts the endogenous bioelectric patterns critical for brain patterning

Summary

Introduction

Endogenous bioelectrical signaling coordinates cell behaviors toward correct anatomical outcomes. Recognized as the key step, but still missing, are biorealistic multi-scale models that integrate cell-level electrophysiology and molecular biology with large-scale patterning information (molecular, anatomical, and bioelectric) Such a synthesis is required in order to explain, in a rigorous manner, how bioelectric events originating with ion channel proteins scale up to regulate emergent organ patterning in health and disease. Nicotine is a well-known neuroteratogen: embryonic exposure to nicotine leads to severe brain morphological defects as well as significant postnatal deficits in cognitive functions[29,30,31,32] The majority of these effects of nicotine occur through its action on nicotinic acetyl choline (nAChR) receptors, but it is not known how this bioelectric change at the single-cell level alters whole organ morphogenesis of the brain. We establish an amphibian model for nicotine teratogenesis, and exploit the Xenopus embryo as proof-of-principle of how computational models of physiological regulatory events can help identify mechanisms of developmental defects and drive the development of therapeutic strategies targeting endogenous bioelectricity

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