Pai VP , Cervera J , Mafe S , Willocq V , Lederer EK , Levin M .

R01 AR055993 NIAMS NIH HHS , R01 AR061988 NIAMS NIH HHS

Xla.wt + nicotine (Fig. 1. L)

	Figure 1. Both local (CNS) and distant (non-CNS) expression of HCN2 channels rescues nicotine-induced brain morphology defects in Xenopus embryos. (A–J) Representative images of stage 45 tadpoles. (A–D) β-galactosidase expression assessed using X-Gal (blue) in bleached tadpole co-injected with Hcn2-WT and β-galactosidase mRNA. β-galactosidase was observed mainly in the eye, brain, and spinal cord (cyan arrowheads), of dorsal blastomere injections. In ventral blastomere injections, β-galactosidase was absent from the eye, brain, and spinal cord (magenta arrowheads) and was mainly present in the brachial arches, gut, heart, and muscles (cyan arrowheads). (E–J) Control (untreated and uninjected) or nicotine-treated tadpoles with or without microinjection with Hcn2-WT mRNA either in dorsal or ventral blastomeres at the four-cell stage. Blue arrowheads indicate intact nostrils, orange brackets indicate intact forebrain (FB), yellow brackets indicate intact midbrain (MB), cyan brackets indicate intact hindbrain (HB), intact eyes (e), and magenta arrowheads indicate severe brain morphology defects. (K–P) Histological staining (hematoxylin and eosin) of agarose sections through the brain (sagittal and transverse sections through midbrain) of stage 45 tadpoles. Control (untreated and uninjected) or nicotine-treated tadpoles with or without microinjection with Hcn2-WT mRNA in the ventral blastomeres at the four-cell stage. FB-forebrain, MB-midbrain, HB-hindbrain, blue arrowheads indicate intact nostrils, and green arrowheads indicate severe brain morphology defects. (Q) Quantification of stage 45 tadpole brain morphology defects under indicated conditions. Percentage of tadpoles with brain defects for each experimental group are Controls—7%, Nicotine—59%, Nicotine+HCN2-WT 2/4 dorsal—27%, Nicotine+HCN2 2/4 ventral—16%, HCN2 2/4 dorsal—5%, HCN2 2/4 ventral—6%, and HCN2-DN—3%. Data are mean ± SD, ****p < 0.0001, ***p < 0.001, **p < 0.01, n.s.: non-significant (one-way ANOVA with Tukey’s post hoc test for n = 3 independent experiments with N > 50 embryos per treatment group per experiment).
	Figure 2. Both local (CNS) and distant (non-CNS) expression of HCN2 channels restore brain size in proportion to head shape in nicotine-exposed embryos. (A–D) Morphometrics canonical variate analysis of brain size in proportion to head shape of stage 45 tadpoles. Representative image of a stage 45 control tadpole (A) illustrating the seven landmarks used in this analysis. (B) Canonical variate analysis, showing confidence ellipses for means at a 0.95 probability of shape data. Confidence ellipses are colored to correspond with treatment as indicated. N > 20 for each group. Procrustes distances: Control vs. nicotine = 0.1, Control vs. nicotine+dorsal-HCN2-WT = 0.04, Control vs. nicotine+ventral-HCN2-WT = 0.05. ANOVA of centroid shape between the controls, nicotine treatment, and nicotine+HCN2-WT (both dorsal and ventral) showed significant differences between the groupings (dorsal microinjection—F = 10.67, p < 0.0001; ventral microinjection—F = 9.0, p < 0.0001). (C,D) Canonical variate axis legend showing the movement of each of the seven landmarks. Each ball represents the landmark as indicated by the number and the accompanying stick represents the direction and extent of movement of that particular landmark.
	Figure 3. Both local (CNS) and distant (non-CNS) HCN2 channel expression restore nicotine exposure-induced mispatterning of brain markers during neural development. (A–H) Representative images of stage 25 embryos as illustrated with the angle of view marked by the black arrow. in situ hybridization with digoxigenin-labeled antisense, riboprobes were used to detect Otx2 and Xbf1 in the indicated experimental groups. Yellow arrows indicate normal expression pattern and magenta arrows indicate significantly mispatterned expression. (I,J) Quantification of in situ hybridized embryos for Otx2 (N ≥ 25 embryos for each experimental group) and Xbf1 (N ≥ 20 embryos for each experimental group) from n = 3 independent experiments pooled together. Data are represented as mean with χ2 squared test for differences in proportions, ***p < 0.001, n.s.: non-significant.
	Figure 4. Both local (CNS) and distant (non-CNS) expression of HCN2 channels restore neural developmental membrane voltage prepatterns in nicotine-exposed embryos. (A–F) Representative CC2-DMPE membrane voltage reporter dye images of stage ~15 Xenopus embryos: Control (untreated and uninjected) or nicotine-treated embryos with or without microinjection with Hcn2-WT mRNA either in dorsal or ventral blastomeres at the four-cell stage. Solid yellow arrows indicate characteristic hyperpolarization in the neural plate as previously reported (Pai et al., 2015b, 2018). Hollow yellow arrows indicate significantly reduced signal (depolarization) within the neural plate in comparison to controls. (G,H) Quantification of fluorescence from CC2-DMPE images of stage 15 Xenopus embryos along with electrophysiology-based membrane voltage approximations [as previously reported in refs (Pai et al., 2015b, 2018)] for the indicated conditions. (G) Quantification obtained along the magenta dotted line indicated in the illustration. (H) Quantification at the point of intersection of the magenta and black dotted line indicated in the illustration. Data represented as mean ± SD, ****p < 0.0001. n.s.: non-significant (one-way ANOVA with Tukey’s post hoc test for N > 5 embryos for each treatment group at each point of the indicated spatial distance).
	Figure 5. Model predicts limiting conditions for distant (non-CNS) HCN2 channel-mediated rescue of membrane voltage prepattern in nicotine-exposed embryos. (A–F) Simulations from a physiological model of neurulating Xenopus embryo as detailed in Supplementary Figures S1–S3. Maroon color represents the region of polarized membrane voltage. Purple color represents the region of depolarized membrane voltage. The pattern in (A) is analogous to the membrane voltage pattern seen in Xenopus embryos with voltage reporter dyes (Pai et al., 2015b).
	Figure 6. HCN2 donor tissue can rescue brain patterning in nicotine-exposed recipient embryos over long distances. (A) Xenopus animal cap transplant experimental setup. The excised animal caps were transplanted into age-matched sibling embryos. (B–G) Representative images of stage 45 tadpoles from transplant receiving host for indicated treatment conditions. Blue arrowheads indicate intact nostrils, orange brackets indicate intact forebrain (FB), yellow brackets indicate intact midbrain (MB), cyan brackets indicate intact hindbrain (HB), and magenta arrowheads indicate severe brain morphology defects. The red region in (E) and (G) is the tomato tracer indicating the transplanted graft. (H) Quantification of stage 45 tadpole brain morphology defects under indicated conditions. Percentage of tadpoles with brain defects for each experimental group are Controls—5%, Nicotine—58%, Nicotine+HCN2-WT-tomato—22%, Nicotine+tomato—59%, and Nicotine+DN-HCN2-tomato—65%. Data are mean ± SD, ***p < 0.001, n.s.: non-significant (one-way ANOVA with Tukey’s post hoc test for n = 3 experiments with N > 20 host embryos per treatment group per experiment). (I,J) Quantification of brain morphology defects in stage 45 tadpoles exposed to nicotine and receiving Hcn2-WT+tomato mRNA expressing tissue transplant. The tadpoles were either sorted by the size of the transplant (I) or location of transplant (J) based on the tomato signal (red) at stage 45. Percentage of tadpoles with brain defects for each experimental group are: Large—27%, Small—83%, Fin—81%, and Near neural—0%. Data pooled from n = 3 independent experiments are represented as mean with χ2 squared test for differences in proportions, ****p < 0.0001, **p < 0.01.
	Figure 7. Non-local exposure to Lamotrigine and Gabapentin (HCN channel agonist) rescues nicotine-induced brain morphology defects in Xenopus embryos. (A—F) Representative images of stage 45 tadpoles. Control (untreated and uninjected) or nicotine-treated tadpoles with or without treatment with lamotrigine (LT, stage 10–35) or gabapentin (GP, stage 10–35). Blue arrowheads indicate intact nostrils, orange brackets indicate intact forebrain (FB), yellow brackets indicate intact midbrain (MB), cyan brackets indicate intact hindbrain (HB), and magenta arrowheads indicate severe brain morphology defects. (G,H) Quantification of stage 45 tadpole brain morphology defects under the indicated conditions for lamotrigine (LT; G) or gabapentin (GP; H). Percentage of tadpoles with brain defects for each experimental group are: (G) Controls—5%, Nicotine—67%, Nicotine+LT (St10–35)—15%, Nicotine+LT (St25–35)—10%, and LT(St 10–35)—2%; (H) Controls—7%, Nicotine—68%, Nicotine+GP (St10–35)—23%, Nicotine+GP(St25–35)—16%, and GP(St 10–35)—11%. Data are mean ± SD, ***p < 0.001, n.s.: non-significant (one-way ANOVA with Tukey’s post hoc test for n = 3 independent experiments with N > 50 embryos per treatment group per experiment).
	Figure 8. Lamotrigine and Gabapentin restore the brain size relation to anterior head shape in nicotine-exposed embryos. (A–D) Morphometrics canonical variate analysis of brain size in proportion to head shape of stage 45 tadpoles. Representative image of a stage 45 control tadpole (A) illustrating the seven landmarks used in this analysis. (B) Canonical variate analysis, showing confidence ellipses for means at a 0.95 probability of shape data. Confidence ellipses are colored to correspond with treatment as indicated. Lamotrigine and gabapentin treatments were from stage 10–35. N > 10 for each group. Procrustes distances: Control vs. nicotine = 0.12, control vs. nicotine+lamotrigine = 0.04, control vs. nicotine+gabapentin = 0.06. ANOVA of centroid shape between the controls, nicotine+lamotrigine, and nicotine+gabapentin in relation to nicotine treatment confirmed significant differences between the groups (F = 8.2, p < 0.0001). (C,D) Canonical variate axis legend showing the movement of each of the seven landmarks. Each ball represents the landmark as indicated by the number and the accompanying stick represents the direction and extent of movement of that particular landmark.
	Figure 9. Lamotrigine and Gabapentin restore neural development membrane voltage prepattern in nicotine-exposed embryos. (A–D) Representative CC2-DMPE membrane voltage reporter dye images of stage ~15 Xenopus embryos: Control (untreated and uninjected) and nicotine-treated embryos with or without lamotrigine (stage 10 onwards) or gabapentin (stage 10 onwards) treatment. Solid yellow arrows indicate characteristic hyperpolarization in the neural plate as previously reported (Pai et al., 2015b, 2018). Hollow yellow arrows indicate significantly reduced signal (depolarization) within the neural plate in comparison to controls. Magenta arrows indicate significantly enhanced hyperpolarization in the neural plate compared to controls. (E,F) Quantification of fluorescence from CC2-DMPE images of stage ~15 Xenopus embryos along with electrophysiology-based membrane voltage approximations [as previously reported in references (Pai et al., 2015b, 2018)] for the indicated conditions (LT-lamotrigine, GP-gabapentin). (E) Quantification obtained along the magenta dotted line indicated in the illustration. (F) Quantification at the point of intersection of the magenta and black dotted line indicated in the illustration. Data represented as mean ± SD, **p < 0.01, ****p < 0.0001 (one-way ANOVA with Tukey’s post hoc test for N > 10 embryos for each treatment group at each point of the indicated spatial distance).
	Figure 10. HCN2 channels (local and distant) and HCN2 channel agonists restore associative learning capacity in nicotine-exposed embryos. Associative learning analysis for stage 45–50 tadpoles with indicated treatments. Lamotrigine (LT, stages 10–35) or gabapentin (GP, stages 10–35). (A) The training regime in the behavior analysis machine consisting of an innate preference test, a training phase (acquisition), a rest period, and a learning probe. Automated software executed a training cycle where animals received a shock when occupying the red half of the arena. Training, rest, and testing sessions were repeated a total of six times across the trial. (B) Quantification of time spent by each tadpole in the red-lit area during the final testing probe for each of the indicated treatments. Percentage of time spent by each tadpole in red light for each experimental group are Controls—24%, Nicotine—60%, Nicotine+HCN2-WT 2/4 dorsal—32%, Nicotine+HCN2-WT 2/4 ventral—27%, Nicotine+LT—28%, and Nicotine+GP—24%. Data represented as mean ± SD, ***p < 0.001, n.s.: non-significant (one-way ANOVA with Tukey’s post hoc test for N > 20 tadpoles for each treatment group).
	Figure 11. Schematic model of bioelectric signaling in brain teratogenesis and long-range repair. (A) Our new data and those of previous studies (Pai et al., 2015b, 2018) show that the membrane voltage difference between the hyperpolarized neural plate and depolarized surrounding ectoderm is crucial for correct gene expression pattern, proper brain morphology, and normal learning behavior. (B) Embryonic nicotine exposure erases this crucial membrane voltage difference and leads to aberrant gene expression patterns, brain morphology defects, and impaired learning behavior. (C) Transplanting HCN2 channel tissue onto nicotine-exposed embryos is sufficient to restore the membrane voltage difference over long-range and rescue gene expression patterns, brain morphology defects and learning behavior in these animals.

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