Thompson AC , Aizenman CD .

R01 EY027380 NEI NIH HHS , R56 NS123565 NINDS NIH HHS

             sodium channel activity
             nervous system development
             neuron development

	Figure 1. Intrinsic excitability of Xenopus tectal neurons is correlated with the amplitude of voltage-gated Na+ currents. (A) Diagram shows a Xenopus tadpole illustrating whole-cell recordings from a neuron of the optic tectum that receives innervation from visual and mechanosensory inputs. (B) Left: example current-clamp recordings showing the spiking response of two stage 49 tectal neurons held at −65 mV to a 50 pA current injection, illustrating the range of responses observed. Middle: plot shows the number of spikes elicited in response to 0–200 pA current injections for all cells analyzed (grey), and the average response (red, mean ± SD). Right: maximum number of spikes (median = 2 spikes, IQR 1–3 spikes, n = 61 cells). (C) Left: example voltage-clamp recording from a tectal neuron held at −65 mV in response to a series of depolarizing steps (−65 to +25 mV). Recording is leak subtracted to show only active currents. Middle: I–V plot shows average current amplitude for the Na+, the transient K+ (KT) and the steady state K+ currents (KSS). Right: peak current amplitudes (Na+: 341.4 ± 176.1 pA; KT: 666.9 ± 281.0 pA; KSS: 517.1 ± 251.2 pA; n = 61 cells). (D, E, F) Plots show Pearson correlations between intrinsic excitability (max. number of spikes) and (D) the amplitude of the Na+ current, (E) the transient K+ current, and (F) the ratio of the Na+ current to transient K+ current. r values are Pearson correlation coefficients (***P = 0.0002; ****P < 0.0001). The complete Pearson correlations matrix showing the relationships between all biophysical properties measured is presented in Fig S1.
	Figure S1. Relationship between biophysical properties of Xenopus tectal neurons at developmental stage 49. Pearson correlation matrix showing the relationship between cell properties for 61 stage 49 tectal neurons. Properties analyzed included neuronal intrinsic excitability (Max # spikes), characteristics of the first spike (spike threshold, spike amplitude, the rate of rise [20–80%], and spike width at 50%), and peak amplitudes for the voltage-gated fast Na+ current (Na+), transient potassium current (KT), and steady state potassium current (KSS). For 40 cells, we measured spike accommodation (Spike accom. = amplitude spike 1/amplitude spike 2), interspike interval (interstimulus intervals [ISI] = time peak of spike 1 − time peak of spike 2). For 22 cells, we measured interspike interval accommodation (ISI accom. = ISI spike 2–3/ISI spike 1–2). Values are Pearson correlation values (r). Bolded values indicate significant Pearson correlations (Bonferroni-corrected P-value < 0.05).
	Figure 3. Tectal neurons express fast and persistent voltage-gated Na+ currents that are regulated with developmental and homeostatic changes in intrinsic excitability. (A) Example voltage-clamp recordings from a tectal neuron held at −65 mV in response to a series of 150 ms depolarizing steps (−65 to 25 mV) using a Tris-based internal saline solution, which blocks outward K+ currents to reveal distinct fast and persistent Na+ currents. Recordings are leak subtracted to show only active currents. Fast (INaF) and persistent (INaP) Na+ currents are indicated on the recording. (B, C) Quantifications of peak amplitudes for the fast and persistent Na+ currents. (B) Fast Na+ current ([in pA] Stage 42: 157.7 ± 32.5; Stage 46: 197.3 ± 64.4; Stage 49: 143.1 ± 60.3; Stage 49 + enhanced visual stimulation [EVS]: 197.4 ± 50.9). (C) Persistent Na+ current ([in pA] Stage 42: 59.8 ± 12.5; Stage 46: 80.7 ± 37.3; Stage 49: 56.3 ± 22.3; Stage 49 + EVS: 73.4 ± 29.0). (D) Example resurgent current recording from a tectal neuron held at −65 mV that was hyperpolarized to −90 mV for 500 ms before stepping to +30 mV for 15 ms to open voltage-gated Na+ channels. Resurgent Na+ currents were then recorded by a repolarizing step to −30 mV for 200 ms, which revealed distinct tail resurgent (RTail), resurgent (R) and persistent resurgent (RPersistent) currents. Recordings were obtained using a Tris-based internal saline solution to block outward K+ currents, and leak subtracted to show only active currents. (E) Averaged resurgent current traces obtained from tectal neurons between developmental stages 42–49, and at stage 49 after exposure to 4 h of EVS. (F) Peak resurgent current amplitude across development and in response to 4 h of EVS ([in pA] Stage 42: 55.9 ± 18.6; Stage 46: 74.3 ± 22.8; Stage 49: 60.0 ± 25.7; Stage 49 + EVS: 78.4 ± 26.9). Groups were compared using a Welch’s ANOVA test with Dunnett T3 test for multiple comparisons. (D) n values are shown in (D).
	Figure S2. Characterizing the voltage and time dependency of the resurgent Na+ current. Resurgent Na+ currents result from a distinctive gating mechanism that traps Na+ channels in a blocked open-state, which is then relieved at depolarized potentials to generate a subthreshold depolarizing current. As a result, resurgent currents display distinct voltage dependency to repolarizing voltage steps, and are affected by the probability of Na+ channels entering the open state (voltage of the depolarizing step) or the inactivated/closed state (time of the depolarizing step). (A, B) The effect of altering the voltage of the repolarizing resurgent step on the identified components of the resurgent current. (A) Example voltage clamp recording showing the response of a single cell when the voltage of the repolarization step was increased from −90 to 20 mV. (B) Plot shows the average voltage dependency of each component of the resurgent current in tectal neurons. (C, D) The effect of altering the time of the depolarizing step on each component of the resurgent current. (C) Example voltage-clamp recording illustrating the response of a single cell when the depolarizing step was increased from 5–35 ms. (D) Plot shows the average voltage response for each component of the resurgent current as the time of the depolarizing step increases. (E, F) The effect of altering the voltage of the resurgent step on each component of the resurgent current. (E) Example voltage-clamp recording showing the response of a single cell when the voltage of the depolarizing step was changed from −20 to 30 mV. (F) Plot illustrates how altering the voltage dependency of the resurgent currents. Plots shown in (B, D, F) are mean ± SD; n = 27 tectal neurons. Resurgent currents are plotted on the left y-axis. Total resurgent current, calculated by measuring the area under the curve or charge (pA*s) over the 200 ms resurgent step, is plotted on the right y-axis.
	Figure S3. Quantification of changes in identified components of the resurgent Na+ current in Xenopus tectal neurons with changes in intrinsic excitability. Quantification of changes in identified components of the resurgent current across development and in response to 4 h of enhanced visual stimulation (EVS). (A) Peak amplitude of the tail resurgent Na+ current (RTail) ([in pA] Stage 42: 75.4 ± 23.7; Stage 46: 84.5 ± 36.7; Stage 49: 73.1 ± 33.5; Stage 49 + EVS: 87.4 ± 40.9). (B) Peak amplitude of the persistent resurgent Na+ current (RPersistent) ([in pA] Stage 42: 22.3 ± 10.8; Stage 46: 34.2 ± 16.7; Stage 49: 27.2 ± 19.7; Stage 49 + EVS: 39.5 ± 27.2). (C) The total resurgent Na+ current (RTotal) ([in pA*s] Stage 42: 5.99 ± 2.55; Stage 46: 9.02 ± 3.54; Stage 49: 6.82 ± 4.07; Stage 49 + EVS: 9.91 ± 5.31). Groups were compared using a Welch’s ANOVA test with Dunnett T3 test for multiple comparisons. n = 24–87 cells.
	Figure S4. Removal of external Na+ specifically inhibits Na+ influx without affecting K+ currents. (A) Example voltage-clamp recordings with a K+-based internal saline in control and Na+ deficient (NMDG) external saline solutions. Magnifications of the initial 30 ms of each trace illustrate how Na+ and K+ currents are temporally isolated in mixed current recordings. (B) I–V plot illustrates the specific effect of removing external Na+ ions on the Na+ currents (circles), sparing the K+ current (squares). (C, D) Quantification of the effect of NMDG external on Na+ currents and K+ currents (****P < 0.0001, n = 7–9 cells).
	Figure 4. The persistent and resurgent Na+ currents, but not the fast Na+ current, are insensitive to tetrodotoxin (TTX). (A, B, C) Example voltage-clamp recordings from tectal neurons with a Tris-based internal solution to isolate Na+ currents from stage 49 tectal neurons in control conditions (black), in zero Na+ external solution (NMDG) to block all inward Na+ currents (grey), in 1 µM TTX to block TTX-sensitive Na+ currents (magenta), or in 100 nM Cd2+ to block Ca2+ currents (cyan). (A) Example recordings show fast and persistent from a single depolarizing step to −15 mV for each experimental group. (A, B) Magnification of the initial 15 ms of the recordings shown in (A) to a series of voltage steps (−65 to +25 mV) to highlight the effect of each treatment on the fast Na+ current. Note that TTX attenuates fast but not persistent Na+ currents, whereas blocking all Na+ influx by replacing external Na+ with NMDG attenuates both fast and persistent currents to reveal a small, presumptive Ca2+ current. (C) Example recordings illustrating the effect of each condition on the resurgent Na+ current. (D, E, F) Quantification of peak amplitudes for the (D) fast, (E) persistent, and (F) resurgent Na+ currents for each experimental group. Groups were compared using a Welch’s ANOVA test with Dunnett T3 test for multiple comparisons. n values for (D, E, F) were 87 stage 49 controls, 15 NMDG, 27 TTX, 11 TTX + Cd2+, and 12 Cd2+. Values and comparisons are shown in Table S2.
	Figure S5. Effect of lidocaine on Na+ currents in tectal neurons. (A) Example voltage-clamp recordings showing the effect of 1 µM lidocaine on the Na+ currents after a 10 s depolarization step to 0 mV, which allows for lidocaine block of open Na+ channels. Recordings were made with a Tris-based internal saline in stage 49 control tectal neurons (black) or tectal neurons exposed to lidocaine (blue). (B) Box indicates portion of each trace shown in (B). (B) Magnification of each trace illustrates how lidocaine affects the fast, persistent, and resurgent Na+ currents. Quantification is shown in Table S2.
	Figure 5. The Nav1.6 specific inhibitor MV1312 decreases intrinsic excitability by reducing fast, persistent, and resurgent Na+ currents in a use-dependent manner. (A) To measure the effect of Nav1.6 channel inhibition on Na+ currents, we performed whole-cell recordings in the presence or absence of 5 µM of the specific Nav1.6 channel inhibitor MV1312. We recorded Na+ currents before and after a 5 s depolarizing step to 0 mV to promote channel opening and drug binding, and then calculated the fraction of each Na+ current that remained. (B, C, D) Quantification of the fraction of initial peak current amplitude for the (B) fast Na+ current (Control: 0.82 ± 0.07, n = 8, MV1312: 0.70 ± 0.04, n = 5; P = 0.0038), (C) persistent Na+ current (Control: 0.73 ± 0.12, MV1312: 0.58 ± 0.10; P = 0.0439), and (D) the resurgent Na+ current (Control: 0.74 ± 0.10, MV1312: 0.38 ± 0.08; P < 0.0001). Groups were compared with an unpaired t test. (E, F) MV1312 decreases intrinsic excitability of tectal neurons by attenuating Na+ current amplitude. (E, F, G) The effect of MV1312 on intrinsic excitability was observed by measuring (E) spikes generated by current injection, (F) the maximum number of spikes generated by current injection (Control: 2.88 ± 1.32, n = 17; MV1312: 1.75 ± 0.72, n = 20; P = 0.0021), and (G) the capacity of cells to spike in response to 200 ms cosine current injections at 30 Hz with increasing amplitudes from 40 to 120 pA (response frequency [% of current injections resulting in a spike]. 40 pA: Control 0.93 ± 0.02, n = 16, MV1312 0.72 ± 0.07, n = 19; P = 0.0002; 80 pA: Control 1.00 ± 0.00, n = 16, MV1312 0.97 ± 0.02, n = 19; P = 0.7429; 120 pA: Control 1.00 ± 0.00, n = 16, MV1312 0.99 ± 0.01, n = 19; P = 0.9712. Groups were compared using a two-way ANOVA with a Holm–Sidak test for multiple comparisons).
	Figure 6. Knockdown of Nav1.6 attenuates network activity-dependent homeostatic increase in Na+ currents. (A) Schematic illustrates how exposure of stage 49 tadpoles to 4 h of enhanced visual stimulation (EVS) decreases excitatory synaptic drive and triggers a compensatory increase in intrinsic excitability via an increase in Na+ currents. (B, C, D) Quantification showing the effect of acute knockdown of expression of specific Nav channel subtypes on the EVS-triggered increases in the amplitude of the fast, persistent, and resurgent Na+ currents. Comparisons between experimental groups are presented in Table S3 (n = 16–22 cells). (E, F, G, H) Exposure of stage 49 tadpoles to 4 h of EVS triggers an increase intrinsic excitability, which is attenuated by the suppression of Nav1.6 channel expression, but not Nav1.1 channel expression (n = 16–31 cells). (I) K+ currents are not regulated with EVS-induced increases in intrinsic excitability. Comparisons between experimental groups are presented in Table S4. Groups were compared using a Welch’s ANOVA test with Dunnett T3 test for multiple comparisons.
	Figure 7. Tadpoles in which expression of Nav1.1 and 1.6 was perturbed during tectal circuit development show impairments in visual acuity, multisensory integration, and schooling behaviors. Effect of knocking down of Nav1.1 and Nav1.6 expression at stages 44–46 on tadpole behavior at stage 49 (comparisons showing that knockdown of Nav1.1 and Nav1.6 expression treatment had no effect on Na+ currents at stage 49 are presented in Table S5). (A, B, C) Effect of developmental knockdown of Nav expression on visual acuity behavior. (A) Control morpholino (Ctrl MO) or Nav1.1/Nav1.6 morpholino (Nav MO) tadpoles were exposed to gratings counterphasing at 4 Hz over a range of spatial frequencies (3, 4.5, 9, and 18 cycles/cm). (B) Knockdown of Nav1.1 and Nav1.6 during the critical period of tectal development impaired responses to low spatial frequencies. Ctrl MO. 3 cycles/cm: 7.0 ± 3.9 (P < 0.0001), 4.5 cycles/cm: 3.5 ± 2.7 (P < 0.0001), 9 cycles/cm: 1.3 ± 1.8 (P = 0.1238), 18 cycles/cm: 0.1 ± 1.4 (P = 0.8330). Nav MO. 3 cycles/cm: 2.6 ± 3.4 (P = 0.0107), 4.5 cycles/cm: 1.0 ± 2.0 (P = 0.9059), 9 cycles/cm: 0.5 ± 1.6 (P = 0.9056), 18 cycles/cm: 0.7 ± 1.8 (P = 0.5767). N = 7 experiments of 3–4 animals. Groups were compared using a two-way ANOVA test with Holm–Sidak test for multiple comparisons. (C) This effect of Nav knockdown on visual acuity was not caused by a change in motility (Ctrl MO: 1.34, IQR = 1.00–1.67; Nav MO: 1.44, IQR = 0.87–1.72; P = 0.8886, n = 25–27 animals). Groups compared using a Mann–Whiney U test. (D, E, F, G, H) Effect of developmental knockdown of Nav expression on multisensory integration behavior. (D) Experimental paradigm illustrating the presentation of visual and mechanosensory stimuli, or multisensory stimuli with interstimulus intervals ranging from 0–500 ms. (E) Mean normalized change in velocity (cm/s) in response to unisensory visual or mechanosensory stimuli, or multisensory stimuli, for Control MO and Nav MO tadpoles. (F) Multisensory (MS) indexes calculated for individual tadpoles at 0, 250, and 500 ms. Values for individual tadpoles are connected by a line. (G) Quantification of MS index for interstimulus intervals of 0 ms (Ctrl MO: 1.1 ± 0.5, Nav MO: 0.4 ± 0.5, P < 0.0001), 250 ms (Ctrl MO: −0.4 ± 0.2, Nav MO: −0.2 ± 0.6, P = 0.0713) and 500 ms (Ctrl MO: 0.6 ± 0.5, Nav MO: 0.3 ± 0.4, P = 0.0438). Groups were compared using Welch’s t test. (H) Histogram of preferred interstimulus intervals for each tadpole. N = 8 experiments of 3–4 animals. (I, J, K) Effect of developmental knockdown of Nav expression on schooling behaviour. (I) Schematic illustrates aggregated schooling behavior observed in control MO and Nav MO tadpoles, with Nav MO tadpoles observed to be less likely to be swimming in the same direction, without a change in inter-tadpole distance. (J, K) These observations are quantified by observing (J) inter-tadpole distance (Ctrl MO: 2.4 cm, IQR = 1.4–3.6 cm; Nav MO: 2.4 cm, IQR = 1.3–3.6 cm; P = 0.4088), and (K) inter-tadpole angles (Ctrl MO: 45.7°, IQR = 19.7–93.9°; Nav MO: 65.6°, IQR = 29.2–119.1°; P < 0.0001). N = 6 experiments of 20 animals per experimental group. Groups were compared using a Kolmogorov–Smirnov test.

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