TABLE 1

Methods of activating and silencing neuronal activity

ToolApproachReferences
Activation
    ChARGeConsists of D. melanogaster Arrestin, Rhodopsin, and G protein; application of light activates rhodopsin and initiates a G protein signaling cascade that results in action potential firing; binding of arrestin to activated rhodopsin stops the signaling cascade; frequency and timing of action potential firing are inconsistent and unpredictable; not feasible for in vivo applicationsZemelman et al., 2002
    FMRF-amide channelPhe-Met-Arg-Phe-amide (FMRFamide)-gated sodium channel from Helix aspersa (HaFaNaC) is activated by FMRFamide; mammals express homologous acid-sensing ion channels (ASICs) but not the ligand FMRFamide; although FMRFamide activates HaFaNaC at lower concentrations than ASICs, extent of cross-reactivity is unknown, as is ability of endogenous mammalian amidated peptides to activate HaFaNaCSchanuel et al., 2008
    Caged glutamateVariety of caged glutamate compounds enable neuronal activation with fast kinetics and single-cell spatial resolutionCanepari et al., 2001; Matsuzaki et al., 2001; Nikolenko et al., 2007; Fino et al., 2009
    Light-gated glutamate receptorA photo-isomerizing glutamate molecule is covalently attached to the outer surface of the binding pocket of an ionotropic glutamate receptor; application of light causes isomerization, brings the glutamate into position in the binding pocket, and opens the cation-selective channelVolgraf et al., 2006; Gorostiza et al., 2007; Szobota et al., 2007; Volgraf et al., 2007; Wang et al., 2007
Silencing
    Ivermectin-gated chloride channelSystem relies on expression of a modified glutamate- and ivermectin-gated chloride channel from C. elegans, GluClαβ; point mutations reduce sensitivity to glutamate; slow onset (4–6 h) and time to peak (12 h) of silencing and prolonged recovery (4 days) with systemic administration; cells must express both α and β subunits (which allows for additional spatial resolution through intersectional expression strategies)Li et al., 2002; Slimko et al., 2002; Slimko and Lester, 2003; Lerchner et al., 2007
    Shibirets1Temperature-sensitive D. melanogaster dynamin mutant gene shibirets1; expression is induced by changes in temperature; expression causes reversible paralysis due to depletion of synaptic vesicles at nerve terminals; specific to D. melanogasterKitamoto, 2001, 2002; Kasuya et al., 2009
    Tetanus toxin light chainTetanus toxin light chain TNT cleaves the synaptic vesicle protein VAMP2/synaptobrevin; TNT expression is inducible; slow recovery (14 days) occurs with VAMP2 resynthesisYamamoto et al., 2003; Yu et al., 2004; Kobayashi et al., 2008; Nakashiba et al., 2008
    Kir2.1Strongly rectifying potassium channel; no cytotoxic potassium leak; channel is constitutively active so reversibility is only achieved through transcriptional controlNitabach et al., 2002; Yu et al., 2004
    Membrane-tethered toxinsPeptide neurotoxins specific for various ion channels can be tethered to the membrane to inactivate ion channels; only reversible through transcriptional regulationIbañez-Tallon et al., 2004; Auer and Ibañez-Tallon, 2010; Auer et al., 2010; Stürzebecher et al., 2010
    5-HT1A8-OH-DPAT is a systemically administrable ligand that selectively activates the Gi-coupled 5-HT1A receptor to activate GIRK and hyperpolarize neuronal membranes; requires 5-HT1A(−/−) backgroundTsetsenis et al., 2007
    GABAA-ZolpidemPositive allosteric GABAA agonists bind benzodiazepine site at interface of α and γ2 subunits; an F77I mutation of γ2 abolishes zolpidem binding; conditional expression of wild-type γ2 on a γ2F77I background enables selective neuronal silencing with zolpidem; the F77I mutation also abolishes binding of an inverse allosteric agonist, suggesting this same method could be used for neuronal activationCope et al., 2004, 2005; Ogris et al., 2004; Wulff et al., 2007; Wisden et al., 2009
  • 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin.