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Beyond the hammer and the scalpel: selective circuit control for the epilepsies

Abstract

Current treatment options for epilepsy are inadequate, as too many patients suffer from uncontrolled seizures and from negative side effects of treatment. In addition to these clinical challenges, our scientific understanding of epilepsy is incomplete. Optogenetic and designer receptor technologies provide unprecedented and much needed specificity, allowing for spatial, temporal and cell type-selective modulation of neuronal circuits. Using such tools, it is now possible to begin to address some of the fundamental unanswered questions in epilepsy, to dissect epileptic neuronal circuits and to develop new intervention strategies. Such specificity of intervention also has the potential for direct therapeutic benefits, allowing healthy tissue and network functions to continue unaffected. In this Perspective, we discuss promising uses of these technologies for the study of seizures and epilepsy, as well as potential use of these strategies for clinical therapies.

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Figure 1: DREADD-mediated attenuation of acute seizures.
Figure 2: On-demand inhibition of spontaneous seizures.

References

  1. 1

    England, M.J., Liverman, C.T., Schultz, A.M. & Strawbridge, L.M. Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav. 25, 266–276 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2

    Perucca, P. & Gilliam, F.G. Adverse effects of antiepileptic drugs. Lancet Neurol. 11, 792–802 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3

    Laxer, K.D. et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 37C, 59–70 (2014).

    Article  Google Scholar 

  4. 4

    Duchowny, M. & Bhatia, S. Epilepsy: preserving memory in temporal lobectomy-are networks the key? Nat. Rev. Neurol. 10, 245–246 (2014).

    Google Scholar 

  5. 5

    de Tisi, J. et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 378, 1388–1395 (2011).

    PubMed  Article  Google Scholar 

  6. 6

    Engel, J. Jr. et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Epilepsia 44, 741–751 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7

    Krook-Magnuson, E., Ledri, M., Soltesz, I. & Kokaia, M. How might novel technologies such as optogenetics lead to better treatments in epilepsy? Adv. Exp. Med. Biol. 813, 319–336 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Wang, J., Faust, S.M. & Rabinowitz, J.E. The next step in gene delivery: molecular engineering of adeno-associated virus serotypes. J. Mol. Cell. Cardiol. 50, 793–802 (2011).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Burger, C. et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol. Therapy 10, 302–317 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Visel, A. et al. A high-resolution enhancer atlas of the developing telencephalon. Cell 152, 895–908 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Zhang, F. et al. Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nat. Protoc. 5, 439–456 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Schnutgen, F. et al. A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nat. Biotechnol. 21, 562–565 (2003).

    PubMed  Article  CAS  Google Scholar 

  13. 13

    Atasoy, D., Aponte, Y., Su, H.H. & Sternson, S.M. A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28, 7025–7030 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Fenno, L.E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Paz, J.T. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat. Neurosci. 16, 64–70 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Armstrong, C., Krook-Magnuson, E., Oijala, M. & Soltesz, I. Closed-loop optogenetic intervention in mice. Nat. Protoc. 8, 1475–1493 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19

    Armbruster, B.N., Li, X., Pausch, M.H., Herlitze, S. & Roth, B.L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl. Acad. Sci. USA 104, 5163–5168 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Guettier, J.M. et al. A chemical-genetic approach to study G protein regulation of beta cell function in vivo. Proc. Natl. Acad. Sci. USA 106, 19197–19202 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Nakajima, K. & Wess, J. Design and functional characterization of a novel, arrestin-biased designer G protein-coupled receptor. Mol. Pharmacol. 82, 575–582 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Katzel, D., Nicholson, E., Schorge, S., Walker, M.C. & Kullmann, D.M. Chemical-genetic attenuation of focal neocortical seizures. Nat. Commun. 5, 3847 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Sukhotinsky, I. et al. Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy model. PLoS ONE 8, e62013 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Berglind, F. et al. Optogenetic inhibition of chemically induced hypersynchronized bursting in mice. Neurobiol. Dis. 65, 133–141 (2014).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Chiang, C.C., Ladas, T.P., Gonzalez-Reyes, L.E. & Durand, D.M. Seizure suppression by high frequency optogenetic stimulation using in vitro and in vivo animal models of epilepsy. Brain Stimulat. 7, 890−899 (2014).

    Article  Google Scholar 

  26. 26

    Wykes, R.C. et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci. Transl. Med. 4, 161ra152 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27

    Krook-Magnuson, E., Szabo, G.G., Armstrong, C., Oijala, M. & Soltesz, I. Cerebellar directed optogenetic intervention inhibits spontaneous hippocampal seizures in a mouse model of temporal lobe epilepsy. eNeruo 1 published online, doi:10.1523/eneuro.0005-14.2014 (December 2014).

  28. 28

    Tonnesen, J., Sorensen, A.T., Deisseroth, K., Lundberg, C. & Kokaia, M. Optogenetic control of epileptiform activity. Proc. Natl. Acad. Sci. USA 106, 12162–12167 (2009).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Selvaraj, P., Sleigh, J.W., Freeman, W.J., Kirsch, H.E. & Szeri, A.J. Open loop optogenetic control of simulated cortical epileptiform activity. J. Comput. Neurosci. 36, 515–525 (2014).

    PubMed  Article  Google Scholar 

  30. 30

    Alexander, G.M. et al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63, 27–39 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Krook-Magnuson, E., Varga, C., Lee, S.H. & Soltesz, I. New dimensions of interneuronal specialization unmasked by principal cell heterogeneity. Trends Neurosci. 35, 175–184 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32

    Lee, S.H. et al. Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells. Neuron 82, 1129–1144 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Brown, S.P. & Hestrin, S. Cell-type identity: a key to unlocking the function of neocortical circuits. Curr. Opin. Neurobiol. 19, 415–421 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Bragin, A., Engel, J. Jr., Wilson, C.L., Vizentin, E. & Mathern, G.W. Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection. Epilepsia 40, 1210–1221 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35

    Haussler, U., Bielefeld, L., Froriep, U.P., Wolfart, J. & Haas, C.A. Septotemporal position in the hippocampal formation determines epileptic and neurogenic activity in temporal lobe epilepsy. Cereb. Cortex 22, 26–36 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36

    Bezaire, M.J. & Soltesz, I. Quantitative assessment of CA1 local circuits: Knowledge base for interneuron-pyramidal cell connectivity. Hippocampus 23, 751−785 (2013).

    PubMed Central  Article  Google Scholar 

  37. 37

    Jiruska, P. et al. Synchronization and desynchronization in epilepsy: controversies and hypotheses. J. Physiol. (Lond.) 591, 787–797 (2013).

    CAS  Article  Google Scholar 

  38. 38

    Coulter, D.A. Algal proteins illuminate epilepsy. Epilepsy Currents 13, 221–223 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Osawa, S. et al. Optogenetically induced seizure and the longitudinal hippocampal network dynamics. PLoS ONE 8, e60928 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Madisen, L. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793–802 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Chuong, A.S. et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat. Neurosci. 17, 1123−1129 (2014).

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  42. 42

    Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Lin, J.Y., Knutsen, P.M., Muller, A., Kleinfeld, D. & Tsien, R.Y. ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nat. Neurosci. 16, 1499–1508 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Zhang, F. et al. Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat. Neurosci. 11, 631–633 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45

    Berndt, A., Lee, S.Y., Ramakrishnan, C. & Deisseroth, K. Structure-guided transformation of channelrhodopsin into a light-activated chloride channel. Science 344, 420–424 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Simonato, M. et al. Progress in gene therapy for neurological disorders. Nat. Rev. Neurology 9, 277–291 (2013).

    CAS  PubMed  Google Scholar 

  47. 47

    Bartus, R.T., Weinberg, M.S. & Samulski, R.J. Parkinson's disease gene therapy: success by design meets failure by efficacy. Mol. Therapy 22, 487–497 (2014).

    CAS  Article  Google Scholar 

  48. 48

    Bartus, R.T. et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 80, 1698–1701 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Murphy, A.M. & Rabkin, S.D. Current status of gene therapy for brain tumors. Transl. Res. 161, 339–354 (2013).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Worgall, S. et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum. Gene Ther. 19, 463–474 (2008).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Kullmann, D.M., Schorge, S., Walker, M.C. & Wykes, R.C. Gene therapy in epilepsy-is it time for clinical trials? Nat. Rev. Neurology 10, 300–304 (2014).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Therapy 17, 1187–1196 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Gray, S.J. et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol. Therapy 18, 570–578 (2010).

    CAS  Article  Google Scholar 

  54. 54

    Drexel, M., Kirchmair, E., Wieselthaler-Holzl, A., Preidt, A.P. & Sperk, G. Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid-induced epilepsy. J. Neuropathol. Exp. Neurol. 71, 312–329 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Han, X. et al. A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex. Front. Syst. Neurosci. 5, 18 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Pei, Y., Rogan, S.C., Yan, F. & Roth, B.L. Engineered GPCRs as tools to modulate signal transduction. Physiology 23, 313–321 (2008).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Kim, T.I. et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340, 211–216 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Stark, E., Koos, T. & Buzsaki, G. Diode probes for spatiotemporal optical control of multiple neurons in freely moving animals. J. Neurophysiol. 108, 349–363 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Cook, M.J. et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol. 12, 563–571 (2013).

    PubMed  Article  Google Scholar 

  60. 60

    Heck, C.N. et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia 55, 432–441 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Wess, J., Nakajima, K. & Jain, S. Novel designer receptors to probe GPCR signaling and physiology. Trends Pharmacol. Sci. 34, 385–392 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

    Jann, M.W., Lam, Y.W. & Chang, W.H. Rapid formation of clozapine in guinea-pigs and man following clozapine-N-oxide administration. Arch. Int. Pharmacodyn. Ther. 328, 243–250 (1994).

    CAS  PubMed  Google Scholar 

  63. 63

    EGFP Collaborative. et al. The epilepsy phenome/genome project. Clin. Trials 10, 568–586 (2013).

  64. 64

    Liu, Y. et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann. Neurol. 74, 128–139 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Henderson, K.W. et al. Long-term seizure suppression and optogenetic analyses of synaptic connectivity in epileptic mice with hippocampal grafts of GABAergic interneurons. J. Neurosci. 34, 13492–13504 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Vezzani, A. The promise of gene therapy for the treatment of epilepsy. Expert Rev. Neurother. 7, 1685–1692 (2007).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Sorensen, A.T. et al. Hippocampal NPY gene transfer attenuates seizures without affecting epilepsy-induced impairment of LTP. Exp. Neurol. 215, 328–333 (2009).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Caroni, P. Overexpression of growth-associated proteins in the neurons of adult transgenic mice. J. Neurosci. Methods 71, 3–9 (1997).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Airan, R.D., Thompson, K.R., Fenno, L.E., Bernstein, H. & Deisseroth, K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Zhang, F. et al. Multimodal fast optical interrogation of neural circuitry. Nature 446, 633–639 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Chow, B.Y. et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps. Nature 463, 98–102 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J. Neurosci. 27, 14231–14238 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    Toettcher, J.E., Weiner, O.D. & Lim, W.A. Using optogenetics to interrogate the dynamic control of signal transmission by the Ras/Erk module. Cell 155, 1422–1434 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472–476 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Motta-Mena, L.B. et al. An optogenetic gene expression system with rapid activation and deactivation kinetics. Nat. Chem. Biol. 10, 196–202 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This work was funded by US National Institutes of Health grants NS35915 and NS74702 (to I.S.), a Citizens United for Research in Epilepsy (CURE) Taking Flight Award (to E.K.-M.), and a US National Institutes of Health grant K99NS087110 (to E.K.-M.).

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Correspondence to Esther Krook-Magnuson or Ivan Soltesz.

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Krook-Magnuson, E., Soltesz, I. Beyond the hammer and the scalpel: selective circuit control for the epilepsies. Nat Neurosci 18, 331–338 (2015). https://doi.org/10.1038/nn.3943

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