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◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✐♥ ▼❛t❧❛❜ ✇✐t❤ P❛♥❞♦r❛✬s ❚♦♦❧❜♦①

❈❡♥❣✐③ ●ü♥❛②

❝❣✉♥❛②❅❡♠♦r②✳❡❞✉

❉❡♣❛rt♠❡♥t ♦❢ ❇✐♦❧♦❣②✱ ❊♠♦r② ❯♥✐✈❡rs✐t②

❖❦✐♥❛✇❛ ❈♦♠♣✳ ◆❡✉r♦s❝✐✳ ❈♦✉rs❡ ✷✵✵✾

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✶ ✴ ✶✸

❲❤② ✇♦✉❧❞ ■ ✉s❡ t❤❡ P❛♥❞♦r❛ t♦♦❧❜♦①❄

P❛♥❞♦r❛ ❝❛♥ ❜❡ ✉s❡❞ ❢♦r✿

✶ ❊①tr❛❝t✐♥❣ ❡❧❡❝tr♦♣❤②s✐♦❧♦❣✐❝❛❧ ♣r♦♣❡rt✐❡s

❡✳❣✳✱ s♣✐❦❡s ❢r♦♠ ❛ ♠❡♠❜r❛♥❡ ✈♦❧t❛❣❡ tr❛❝❡

✷ ❉❛t❛❜❛s❡ ❛♥❛❧②s✐s ♦❢ ♠♦❞❡❧ ♦r ❡①♣❡r✐♠❡♥t❛❧ ❞❛t❛

❈r❡❛t✐♥❣ ❛ ❞❛t❛❜❛s❡ ❢r♦♠ ❛♥② ❞❛t❛ ❢♦r q✉❡r②✐♥❣ ❛♥❞ ♣❧♦tt✐♥❣✳ P✉tt✐♥❣ r❡s✉❧ts ❢r♦♠ ❛♥❛❧②s✐s ♦❢ ✈♦❧t❛❣❡ tr❛❝❡s ♦❢ ♠✉❧t✐♣❧❡ ♠♦❞❡❧s ✐♥t♦ ❛ ❞❛t❛❜❛s❡✳ ❆❞✈❛♥❝❡❞ ♦♣❡r❛t✐♦♥s ✇✐t❤ ❛ ❞❛t❛❜❛s❡✿ st❛t✐st✐❝s✱ ♠✉❧t✐✈❛r✐❛t❡ ❛♥❛❧②s✐s✱ ❡t❝✳ P❛♥❞♦r❛✬s ♣❧♦tt✐♥❣ ❢✉♥❝t✐♦♥s ✭❝❛♥ ❛❧s♦ ❜❡ ✉s❡❞ ♦✉ts✐❞❡ ♦❢ ❞❛t❛❜❛s❡s✮✳

❙❡❡ ●ü♥❛② ❡t ❛❧✳ ✭✷✵✵✾✮ ◆❡✉r♦✐♥❢♦r♠❛t✐❝s❀ ❛❧s♦ ❅ ■◆❈❋ ❙♦❢t✇❛r❡ ❈❡♥t❡r ❛♥❞ ❖❈◆❈ ❢♦r✉♠✳

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✷ ✴ ✶✸

❲❤❛t ✐s t❤❡ P❛♥❞♦r❛ t♦♦❧❜♦①❄

▼❛✐♥ ❝♦♠♣♦♥❡♥ts ♦❢ P❛♥❞♦r❛✿

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✸ ✴ ✶✸

▲♦❛❞✐♥❣ ❛ ♠❡♠❜r❛♥❡ ✈♦❧t❛❣❡ tr❛❝❡

P❛♥❞♦r❛ ❝❛♥ r❡❛❞ t❤❡ ✜❧❡ ❢♦r♠❛ts ❢r♦♠✿

✶ ❙✐♠✉❧❛t♦rs✿

◆❡✉r♦♥

• ❡♥❡s✐s

✷ ❉❛t❛ ❛❝q✉✐s✐t✐♦♥ ♣r♦❣r❛♠s✿

❆❧❧ ◆❡✉r♦❙❤❛r❡✲❝♦♠♣❛t✐❜❧❡ ❛❝q✉✐s✐t✐♦♥ ❞❡✈✐❝❡s ✭❆❧♣❤❛ ❖♠❡❣❛✱ ❈❛♠❜r✐❞❣❡ ❊❧❡❝tr♦♥✐❝ ❉❡s✐❣♥✱ ◆❡✉r♦❊①♣❧♦r❡r✱ P❧❡①♦♥✱ ❘✳❈✳ ❊❧❡❝tr♦♥✐❝s ■♥❝✳✱ ❚✉❝❦❡r✲❉❛✈✐s ❚❡❝❤♥♦❧♦❣✐❡s✱ ❛♥❞ ❈②❜❡r❦✐♥❡t✐❝s ■♥❝✳✱ ❡t❝✳✮

✸ ❖t❤❡r✿

❍✐❡r❛r❝❤✐❝❛❧ ❞❛t❛ ❢♦r♠❛t ✭❍❉❋✺✮

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✹ ✴ ✶✸

❆♥❛❧②③✐♥❣ ❛ ♠❡♠❜r❛♥❡ ✈♦❧t❛❣❡ tr❛❝❡

❇② ❡①tr❛❝t✐♥❣ ❡❧❡❝tr♦♣②s✐♦❧♦❣✐❝❛❧ ❝❤❛r❛❝t❡r✐st✐❝s

▼❡❛s✉r❡ s♣✐❦❡ s❤❛♣❡ ❛♥❞ ✜r✐♥❣ r❛t❡ ♣r♦♣❡rt✐❡s ▼❡❛s✉r❡ s❛❣✱ s♣✐❦❡ ❛❞❛♣t❛t✐♦♥ ❛♥❞ ❝✉rr❡♥t r❡s♣♦♥s❡ ♣r♦♣❡rt✐❡s ❈❛♥ ❜❡ ❞♦♥❡ r❡♣❡t✐t✐✈❡❧② ❢♦r ❛ ❧❛r❣❡ ♥✉♠❜❡r ♦❢ ♠♦❞❡❧s ❈❛♥ ❜❡ ❡♥t❡r❡❞ ✐♥t♦ ❛ ▼❛t❧❛❜ ❞❛t❛❜❛s❡ ❉❊▼❖

1450 1500 1550 −100 −90 −80 −70 −60 annotated spike characteristics time [ms] voltage [mV]

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✺ ✴ ✶✸

❈r❡❛t✐♥❣ ❛ ❞❛t❛❜❛s❡ ❢r♦♠ ❛r❜✐tr❛r② ❞❛t❛

❈r❡❛t❡ ❛ ✷×✷ ❞❛t❛❜❛s❡ ♠❛tr✐①✿ ❲✐t❤ ▼❛t❧❛❜ ❝♦❞❡✿ ❃✗❃ ❞❜❴♦❜❥ ❂ t❡sts❴❞❜✭❬✶ ✷❀ ✸ ✹❪✱ ④✬❝♦❧✶✬✱ ✬❝♦❧✷✬⑥✱ ④✬r♦✇✶✬✱ ✬r♦✇✷✬⑥✱ ✬❛ ✷①✷ ❉❇✬✮

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✻ ✴ ✶✸

❈r❡❛t✐♥❣ ❛ ❞❛t❛❜❛s❡ ❢r♦♠ ❛♥❛❧②s✐s ♦❢ tr❛❝❡s

❯s✐♥❣ ❛ ❞❛t❛s❡t✿ ✶ ❃❃ ♠②❴❞❛t❛s❡t❴♦❜❥ ❂ ♠②❴❞❛t❛s❡t❴❝❧❛ss ✭ ✬ ❞❛t❛ ✴∗✳ ❜✐♥ ✬ ✱ ❛r❣✉♠❡♥ts ✳ ✳ ✳ ✮ ✸ ❃❃ ♠②❴❞❛t❛❜❛s❡❴♦❜❥ ❂ ♣❛r❛♠❴t❡sts❴❞❜ ✭ ♠②❴❞❛t❛s❡t❴♦❜❥ ✮ ✺ ❃❃ s♦rt❡❞❴♦❜❥ ❂ s♦rtr♦✇s ✭ ♠②❴❞❛t❛❜❛s❡❴♦❜❥ ✱ ✬ ❆P❴❛♠♣❧✐t✉❞❡ ✬ ✮

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✼ ✴ ✶✸

❉❛t❛❜❛s❡ ❛♥❛❧②s✐s✿ ◗✉❡r②✐♥❣

❃❃ ❞❜❴♦❜❥✷ ❂ ✷ ❞❜❴♦❜❥ ✭✶✿✶✵ ✱ ④ ✬ ♥❡✉r♦♥❴✐♥❞❡① ✬ ✱ ✬ ❢ ✐ r ❡ ❴ r ❛ t ❡ ✬ ⑥✮ ❃❃ ❞❜❴♦❜❥✷ ❂ ✹ ❞❜❴♦❜❥ ✭ ❞❜❴♦❜❥ ✭ ✿ ✱ ✬ ♥❡✉r♦♥❴✐♥❞❡① ✬ ✮ ❂❂ ✹✻ ✱ ✿ ✮ ❃❃ ❞❜❴♦❜❥✷ ❂ ✻ ❞❜❴♦❜❥ ✭ ❛♥②❘♦✇s ✭ ❞❜❴♦❜❥ ✭ ✿ ✱ ✬ ♥❡✉r♦♥❴✐♥❞❡① ✬ ✮ ✱ ❬ ✹ ✻ ❀ ✺✻❀ ✶✷❪✮ ✱ ✿ ✮ ✽ ❃❃ ❞❜❴♦❜❥✷ ❂ ❞❜❴♦❜❥ ✭ ❞❜❴♦❜❥ ✭ ✿ ✱ ✬ ♥❡✉r♦♥❴✐♥❞❡① ✬ ✮ ⑦❂ ✹✻ ✫ ✶✵ ✭ ❞❜❴♦❜❥ ✭ ✿ ✱ ✬ ❈■P ✬ ✮ ❃ ✶✵✵ ⑤ ❞❜❴♦❜❥ ✭ ✿ ✱ ✬ r ❛ t ❡ ✬ ✮ ❁❂ ✺✵ ✮ ✱ ✿ ✮ ✱ ✶✷ ❃❃ ❞❜❴♦❜❥✷ ❂ ♠♦❞❡❧❴❞❜❴♦❜❥ ✭ ❛♥②❘♦✇s ✭ ♠♦❞❡❧❴❞❜❴♦❜❥ ✭ ✿ ✱ ✬ r ❛ t ❡ ✬ ✮ ✱ ✶✹ ♥❡✉r♦♥❴❞❜❴♦❜❥ ✭ ✿ ✱ ✬ r ❛ t ❡ ✬ ✮✮ ✱ ✿ ✮

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✽ ✴ ✶✸

▼✉❧t✐✈❛r✐❛t❡ ❛♥❛❧②s✐s

❚❡tr♦❞♦t♦①✐♥ ❜❧♦❝❦ ❡✛❡❝ts ♦♥ ✜r✐♥❣ r❛t❡ ♦❢ ❣❧♦❜✉s ♣❛❧❧✐❞✉s ♥❡✉r♦♥s ✇✐t❤ ❝✉rr❡♥t ✐♥❥❡❝t✐♦♥

7e−09 20 22 24 26 28 30

n=3 n=3

TTX [M] steady−rate (+100pA) [Hz] 1 −7 −6 −5 −4 −3 rate change with 0 to 7 nM TTX [Hz] ❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✾ ✴ ✶✸

▼✉❧t✐✈❛r✐❛t❡ ❛♥❛❧②s✐s ✭■✮

❙✐❢t✐♥❣ t❤❡ ❞❛t❛❜❛s❡ t♦ ✜♥❞ ❡✛❡❝ts ♦❢ ♣❛r❛♠❡t❡rs

❙❛♠♣❧❡ ✇✐t❤ ✸ ◆❡✉r♦♥s✿

P✐❝r♦❚① ✵.✵✵✵✶ ✵.✵✵✵✶ ✵.✵✵✵✶ ✵.✵✵✵✶ ✵.✵✵✵✶ ✵.✵✵✵✶ ❑②♥❆❝✐❞ ✵.✵✵✶ ✵.✵✵✶ ✵.✵✵✶ ✵.✵✵✶ ✵.✵✵✶ ✵.✵✵✶ ❚❚❳ ✵ ✼❡ −✵✾ ✵ ✼❡ −✵✾ ✵ ✼❡ −✵✾ ❆♣❛♠✐♥ ✵ ✵ ✵ ✵ ✵ ✵ ❞r✉❣ ✹❆P ✵ ✵ ✵ ✵ ✵ ✵ ◆❡✉r♦♥■❞ ✶✵✼ ✶✵✼ ✶✵✽ ✶✵✽ ✶✶✵ ✶✶✵ ❉✶✵✵♣❆ st❡❛❞② r❛t❡ ✷✺.✾✾✽✷ ✶✾.✻✵✺✻ ✷✾.✾✻✼✸ ✷✷.✼✻✷✽ ✷✸.✽✹✹✸ ✷✵.✾✼✹✹

❋♦❝✉s ♦♥ ❝❤❛♥❣❡s ✇✐t❤ ❚❚❳✿

P❛❣❡ ✶ P❛❣❡ ✷ P❛❣❡ ✸ ❚❚❳ ✵ ✼❡ −✵✾ ✵ ✼❡ −✵✾ ✵ ✼❡ −✵✾ ❉✶✵✵♣❆ st❡❛❞② r❛t❡ ✷✺.✾✾✽✷ ✶✾.✻✵✺✻ ✷✾.✾✻✼✸ ✷✷.✼✻✷✽ ✷✸.✽✹✹✸ ✷✵.✾✼✹✹ ❘♦✇■♥❞❡① ✶ ✷ ✸ ✹ ✺ ✻

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✶✵ ✴ ✶✸

▼✉❧t✐✈❛r✐❛t❡ ❛♥❛❧②s✐s ✭■■✮

Pr♦❝❡ss✐♥❣ ❞❛t❛❜❛s❡ ❝♦♥t❡♥ts

❈❤❛♥❣❡ ✐♥ r❛t❡ ✭∆✮ ❜❡t✇❡❡♥ s✉❝❝❡ss✐✈❡ ❚❚❳ ❧❡✈❡❧s✿ ❞✶❴✷ −✻.✸✾✷✻ −✼.✷✵✹✺ −✷.✽✻✾✾ P❛❣❡■♥❞❡① ✶ ✷ ✸ ❘❡❣r♦✉♣✐♥❣ t♦ ✜♥❞ ❛✈❡r❛❣❡ ✈❛❧✉❡s ❢♦r ❡❛❝❤ ❚❚❳ ❧❡✈❡❧✿

P❛❣❡ ✶ P❛❣❡ ✷ ❚❚❳ ✵ ✵ ✵ ✼❡ −✵✾ ✼❡ −✵✾ ✼❡ −✵✾ ❉✶✵✵♣❆ st❡❛❞② r❛t❡ ✷✺.✾✾✽✷ ✷✾.✾✻✼✸ ✷✸.✽✹✹✸ ✶✾.✻✵✺✻ ✷✷.✼✻✷✽ ✷✵.✾✼✹✹ ❘♦✇■♥❞❡① ✶ ✸ ✺ ✷ ✹ ✻

❉❊▼❖

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✶✶ ✴ ✶✸

❈r❡❞✐ts

Pr♦❣r❛♠♠❡rs✴t❡st✐♥❣✿ ❏❡r❡♠② ❘✳ ❊❞❣❡rt♦♥✱ P❤✳❉✳ ❚❤♦♠❛s ❙❛♥❣r❡②✱ P❤✳❉✳ ▲✐✱ ❙✉✱ P❤✳❉✳ ❙✉♣❡r✈✐s♦rs✿ ❉✐❡t❡r ❏❛❡❣❡r✱ P❤✳❉✳ ❆str✐❞ ❆✳ Pr✐♥③✱ P❤✳❉✳

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✶✷ ✴ ✶✸

❈♦♥t❡♥ts

✶

❖✈❡r✈✐❡✇ ❲❤❛t ✐s P❛♥❞♦r❛❄

✷

❆♥❛❧②③✐♥❣ ✈♦❧t❛❣❡ tr❛❝❡ ❞❛t❛ ▲♦❛❞✐♥❣ ❛ ♠❡♠❜r❛♥❡ ✈♦❧t❛❣❡ tr❛❝❡ ❆♥❛❧②③✐♥❣ ❛ ♠❡♠❜r❛♥❡ ✈♦❧t❛❣❡ tr❛❝❡

✸

❉❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❈r❡❛t✐♥❣ ❛ ❞❛t❛❜❛s❡ ❢r♦♠ ❛r❜✐tr❛r② ❞❛t❛ ❈r❡❛t✐♥❣ ❛ ❞❛t❛❜❛s❡ ❢r♦♠ ❛♥❛❧②s✐s ♦❢ tr❛❝❡s

❈✳ ●ü♥❛② ✭❊♠♦r② ❯♥✐✈❡rs✐t②✮ ◆❡✉r❛❧ ❞❛t❛❜❛s❡ ❛♥❛❧②s✐s ✇✐t❤ P❛♥❞♦r❛ ❖❈◆❈ ✷✵✵✾ ✶✸ ✴ ✶✸