HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns

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.

Preventing Ethanol-Induced Brain and Eye Morphology Defects Using Optogenetics

“…[32][33][34][35] Moreover, reinforcing these endogenous membrane voltage patterns rescues eye and brain defects caused by mutant notch and teratogen nicotine. 34,42,43 These experiments show that the bioelectric prepattern is necessary and sufficient for normal eye and brain morphogenesis as well as normal expression of the patterning genes.…”

“…52,53 We saw the normal, low background levels of brain and eye anomalies (<9%), indicating good animal health and good rearing conditions. At stage 45, large-scale brain and eye patterning and anomalies in gross morphology were as-sessed as before 32,34,42 and using Refs. 18,49,50,52,54 All experiments were approved by the Tufts University Animal Research Committee (Protocol M2017-53A) in accordance with the Guide for Care and Use of Laboratory Animals.…”

The Biophysics of Regenerative Repair Suggests New Perspectives on Biological Causation

“…This pattern is abolished by teratogens and mutations of genes like the important neurogenesis gene Notch (C’). Indeed, artificially enforcing the bioelectric difference via misexpression of an HCN2 channel, which works like a contrast enhancer to strengthen differences at the edge eroded by teratogenic influences, rescues brain patterning (C”), gene expression, and behavioral function . Reproduced with permission .…”

“…Indeed, amplifying this voltage difference proved successful in repairing birth defects (Figure 5C –C”), even ones induced by a dominant mutation of Notch —an important neurogenesis gene, showing that physiological signals can sometimes override genome‐default states (a theme also observed in recent experiments inducing genetically wild‐type planaria to grow heads resembling those of other species). Crucially, these approaches do not require genomic editing and do not rely on any one specific gene product: a wide range of ion channel proteins (and channel‐modifying compounds, including those generated by commensal microbiota) can be used by the experimenter to rationally alter the stable modes of the bioelectric network that drive downstream changes in gene expression and cell behavior.…”

Post-SSRI Sexual Dysfunction: A Bioelectric Mechanism?

“…106 Paralleling the development of ion channel modulator drug cocktails, guided by computational models of bioelectric circuits to induce desired pro-regenerative states, it's possible that the negative effects of SSRI exposure could someday be mitigated by rationally designed cocktails of already humanapproved drugs acting as ionoceuticals. 107,108…”