Communication between populations of physically interconnected neurons defines a recognizable neuronal circuit. Contemporary genetic methods allow targeting specific cell types within complex neural circuits, but few methods are available to manipulate and observe neural circuits in action. For this purpose, we have recently developed a strategy that blocks ion channels with genetically expressed cell-membrane bound neurotoxins. This idea originated from our previous discovery of an endogenous prototoxin, lynx1, which modulates nicotinic receptors, nAChRs. By tethering venom neurotoxins to the cell membrane we can exploit their discriminative and high blocking capability but restrict their action to ion channels and receptors coexpressed in the same cell. The ongoing projects in our group are aimed at either silencing or manipulating specific ion channels in defined neuronal circuits in the mouse nervous system. The questions we are addressing are: how a particular class of ion channels in one cell population contributes to the function of a given neuronal circuit, and whether silencing one cell population has an impact in only that circuit and/or also affects the next circuit. Another question of interest is whether these functions can be restored upon reversibly inhibiting the expression of the toxin. To approach these questions, we are focusing on specific neuronal circuits in which manipulation of certain ion channels could help dissecting the cascade of events that leads to chronic pain, hearing impairment, and nicotine mediated effects. To target these circuits, we are using two complementary approaches: one employs BAC transgenesis to achieve cell-specific and stable expression, the second uses lentiviral vectors that are microinjected directly into specific brain areas in the mouse. These studies provide a new framework for in vivo manipulating ion channels and diseases of electrical excitability.
Lechner SG, Markworth S, Poole K, Smith ES, Lapatsina L, Frahm S, May M, Pischke S, Suzuki M, Ibañez-Tallon I, Luft FC, Jordan J, Lewin GR. (2011)
The molecular and cellular identity of peripheral osmoreceptors.
Auer, S and Stuerzebecher, AS and Juettner, R and Santos-Torres, J and Hanack, C and Frahm, S and Liehl, B and Ibañez-Tallon I (2010)
Silencing neurotransmission with membrane-tethered toxins.
Nat. Methods 7 (3): 229-236.
Stuerzebecher, AS and Hu, J and Smith, ESJ and Frahm, S and Santos-Torres, J and Kampfrath, B and Auer, S and Lewin, GR and Ibañez-Tallon I (2010)
An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors.
Journal of Physiology 588 (Pt 10): 1695-1707
Holford, M and Auer, S and Laqua, M and Ibañez-Tallon I (2009) Manipulating neuronal circuits with endogenous and recombinant cell-surface tethered modulators. Frontiers in Molecular Neurosciences 2 : 21
Hruska, M and Nishi, R and Ibañez-Tallon I (2007)
Cell-autonomous inhibition of alpha 7-containing nicotinic acetylcholine receptors prevents death of parasympathetic neurons during development.
J Neuroscience 27 (43): 11501-11509
Miwa JM, Stevens TR, King SL, Caldarone BJ, Ibanez-Tallon I, Xiao C, Fitzsimonds RM, Pavlides C, Lester HA, Picciotto MR, Heintz N.
The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo.
Neuron. 2006 Sep 7;51(5):587-600.
Ibañez-Tallon I, Wen H, Miwa JM, Xing J, Tekinay AB, Ono F, Brehm P, Heintz N.(2004)
Tethering naturally occurring peptide toxins for cell-autonomous modulation of ion channels and receptors in vivo.
Neuron. Aug 5;43(3):305-11.