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Microcircuits and their interactions in epilepsy: is the focus out of focus?

Abstract

Epileptic seizures represent dysfunctional neural networks dominated by excessive and/or hypersynchronous activity. Recent progress in the field has outlined two concepts regarding mechanisms of seizure generation, or ictogenesis. First, all seizures, even those associated with what have historically been thought of as 'primary generalized' epilepsies, appear to originate in local microcircuits and then propagate from that initial ictogenic zone. Second, seizures propagate through cerebral networks and engage microcircuits in distal nodes, a process that can be weakened or even interrupted by suppressing activity in such nodes. We describe various microcircuit motifs, with a special emphasis on one that has been broadly implicated in several epilepsies: feed-forward inhibition. Furthermore, we discuss how, in the dynamic network in which seizures propagate, focusing on circuit 'choke points' remote from the initiation site might be as important as that of the initial dysfunction, the seizure 'focus'.

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Figure 1: Microcircuit motifs whose dysfunctions have been identified in epilepsy.
Figure 2: Feed-forward inhibition in cortical and thalamic microcircuits.
Figure 3: Feed-back inhibition in cortical and thalamic microcircuits.
Figure 4: Counter-inhibition in hippocampal and thalamic microcircuits.
Figure 5: Recurrent excitation in cortex and hippocampus.
Figure 6: Circuit therapy: focus on choke points.

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References

  1. Avoli, M. A brief history on the oscillating roles of thalamus and cortex in absence seizures. Epilepsia 53, 779–789 (2012).

    PubMed  PubMed Central  Google Scholar 

  2. Noebels, J.L., Avoli, M., Rogawski, M.A., Olsen, R.W. & Delgado-Escueta, A.V. Jasper's Basic Mechanisms of the Epilepsies (National Center for Biotechnology Information, Bethesda, 2012).

    Google Scholar 

  3. Jones, E.G. The Thalamus (Cambridge University Press, 2007).

    Google Scholar 

  4. Douglas, R.J. & Martin, K.A. A functional microcircuit for cat visual cortex. J. Physiol. (Lond.) 440, 735–769 (1991).

    CAS  Google Scholar 

  5. Douglas, R.J., Koch, C., Mahowald, M., Martin, K.A. & Suarez, H.H. Recurrent excitation in neocortical circuits. Science 269, 981–985 (1995).

    CAS  PubMed  Google Scholar 

  6. Gabernet, L., Jadhav, S.P., Feldman, D.E., Carandini, M. & Scanziani, M. Somatosensory integration controlled by dynamic thalamocortical feed-forward inhibition. Neuron 48, 315–327 (2005).

    CAS  PubMed  Google Scholar 

  7. Sun, Q.Q., Huguenard, J.R. & Prince, D.A. Reorganization of barrel circuits leads to thalamically-evoked cortical epileptiform activity. Thalamus Relat. Syst. 3, 261–273 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sun, Q.Q., Huguenard, J.R. & Prince, D.A. Barrel cortex microcircuits: thalamocortical feedforward inhibition in spiny stellate cells is mediated by a small number of fast-spiking interneurons. J. Neurosci. 26, 1219–1230 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ewell, L.A. & Jones, M.V. Frequency-tuned distribution of inhibition in the dentate gyrus. J. Neurosci. 30, 12597–12607 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Xiang, Z., Huguenard, J.R. & Prince, D.A. Cholinergic switching within neocortical inhibitory networks. Science 281, 985–988 (1998).

    CAS  PubMed  Google Scholar 

  11. Xiang, Z., Huguenard, J.R. & Prince, D.A. Synaptic inhibition of pyramidal cells evoked by different interneuronal subtypes in layer v of rat visual cortex. J. Neurophysiol. 88, 740–750 (2002).

    PubMed  Google Scholar 

  12. Molnár, G. et al. Complex events initiated by individual spikes in the human cerebral cortex. PLoS Biol. 6, e222 (2008).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bagnall, M.W., Hull, C., Bushong, E.A., Ellisman, M.H. & Scanziani, M. Multiple clusters of release sites formed by individual thalamic afferents onto cortical interneurons ensure reliable transmission. Neuron 71, 180–194 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Swadlow, H.A. & Gusev, A.G. Receptive-field construction in cortical inhibitory interneurons. Nat. Neurosci. 5, 403–404 (2002).

    CAS  PubMed  Google Scholar 

  16. Porter, J.T., Johnson, C.K. & Agmon, A. Diverse types of interneurons generate thalamus-evoked feedforward inhibition in the mouse barrel cortex. J. Neurosci. 21, 2699–2710 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Somogyi, P., Kisvarday, Z.F., Martin, K.A. & Whitteridge, D. Synaptic connections of morphologically identified and physiologically characterized large basket cells in the striate cortex of cat. Neuroscience 10, 261–294 (1983).

    CAS  PubMed  Google Scholar 

  18. Inoue, T. & Imoto, K. Feedforward inhibitory connections from multiple thalamic cells to multiple regular-spiking cells in layer 4 of the somatosensory cortex. J. Neurophysiol. 96, 1746–1754 (2006).

    PubMed  Google Scholar 

  19. Maheshwari, A., Nahm, W.K. & Noebels, J.L. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice. Front. Cell. Neurosci. 7, 156 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Sasaki, S., Huda, K., Inoue, T., Miyata, M. & Imoto, K. Impaired feedforward inhibition of the thalamocortical projection in epileptic Ca2+ channel mutant mice, tottering. J. Neurosci. 26, 3056–3065 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Paz, J.T. et al. A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy. Nat. Neurosci. 14, 1167–1173 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sloviter, R.S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1, 41–66 (1991).

    CAS  PubMed  Google Scholar 

  23. Bekenstein, J.W. & Lothman, E.W. Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy. Science 259, 97–100 (1993).

    CAS  PubMed  Google Scholar 

  24. Cammarota, M., Losi, G., Chiavegato, A., Zonta, M. & Carmignoto, G. Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy. J. Physiol. (Lond.) 591, 807–822 (2013).

    CAS  Google Scholar 

  25. Sah, N. & Sikdar, S.K. Transition in subicular burst firing neurons from epileptiform activity to suppressed state by feedforward inhibition. Eur. J. Neurosci. 38, 2542–2556 (2013).

    PubMed  Google Scholar 

  26. Khalilov, I., Holmes, G.L. & Ben Ari, Y. In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat. Neurosci. 6, 1079–1085 (2003).

    CAS  PubMed  Google Scholar 

  27. Rossignol, E., Kruglikov, I., van den Maagdenberg, A.M., Rudy, B. & Fishell, G. CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Ann. Neurol. 74, 209–222 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tai, C., Abe, Y., Westenbroek, R.E., Scheuer, T. & Catterall, W.A. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. Proc. Natl. Acad. Sci. USA 111, E3139–E3148 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yamakawa, K. Molecular and cellular basis: insights from experimental models of Dravet syndrome. Epilepsia 52 Suppl 2, 70–71 (2011).

    PubMed  Google Scholar 

  30. Dutton, S.B. et al. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility. Neurobiol. Dis. 49, 211–220 (2013).

    CAS  PubMed  Google Scholar 

  31. Verret, L. et al. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149, 708–721 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Walker, J., Storch, G., Quach-Wong, B., Sonnenfeld, J. & Aaron, G. Propagation of epileptiform events across the corpus callosum in a cingulate cortical slice preparation. PLoS ONE 7, e31415 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Du, F., Eid, T., Lothman, E.W., Kohler, C. & Schwarcz, R. Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy. J. Neurosci. 15, 6301–6313 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. van Groen, T., Miettinen, P. & Kadish, I. The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation. Hippocampus 13, 133–149 (2003).

    PubMed  Google Scholar 

  35. Dinocourt, C., Petanjek, Z., Freund, T.F., Ben Ari, Y. & Esclapez, M. Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine-induced seizures. J. Comp. Neurol. 459, 407–425 (2003).

    PubMed  Google Scholar 

  36. Leão, R.N. et al. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. Nat. Neurosci. 15, 1524–1530 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. Cossart, R. et al. Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat. Neurosci. 4, 52–62 (2001).

    CAS  PubMed  Google Scholar 

  38. Maccaferri, G. & McBain, C.J. Passive propagation of LTD to stratum oriens-alveus inhibitory neurons modulates the temporoammonic input to the hippocampal CA1 region. Neuron 15, 137–145 (1995).

    CAS  PubMed  Google Scholar 

  39. Ang, C.W., Carlson, G.C. & Coulter, D.A. Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy. J. Neurosci. 26, 11850–11856 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Peng, Z. et al. A reorganized GABAergic circuit in a model of epilepsy: evidence from optogenetic labeling and stimulation of somatostatin interneurons. J. Neurosci. 33, 14392–14405 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Prince, D.A. & Wilder, B.J. Control mechanisms in cortical epileptogenic foci. “Surround” inhibition. Arch. Neurol. 16, 194–202 (1967).

    CAS  PubMed  Google Scholar 

  42. Dichter, M. & Spencer, W.A. Penicillin-induced interictal discharges from the cat hippocampus. I. Characteristics and topographical features. J. Neurophysiol. 32, 649–662 (1969).

    CAS  PubMed  Google Scholar 

  43. Trevelyan, A.J., Sussillo, D. & Yuste, R. Feedforward inhibition contributes to the control of epileptiform propagation speed. J. Neurosci. 27, 3383–3387 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Schevon, C.A. et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat. Commun. 3, 1060 (2012).

    PubMed  Google Scholar 

  45. Vigeland, L.E., Contreras, D. & Palmer, L.A. Synaptic mechanisms of temporal diversity in the lateral geniculate nucleus of the thalamus. J. Neurosci. 33, 1887–1896 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Golshani, P., Liu, X.B. & Jones, E.G. Differences in quantal amplitude reflect GluR4- subunit number at corticothalamic synapses on two populations of thalamic neurons. Proc. Natl. Acad. Sci. USA 98, 4172–4177 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lacey, C.J., Bryant, A., Brill, J. & Huguenard, J.R. Enhanced NMDA receptor–dependent thalamic excitation and network oscillations in stargazer mice. J. Neurosci. 32, 11067–11081 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Beyer, B. et al. Absence seizures in C3H/HeJ and knockout mice caused by mutation of the AMPA receptor subunit Gria4. Hum. Mol. Genet. 17, 1738–1749 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Andolina, I.M., Jones, H.E. & Sillito, A.M. Effects of cortical feedback on the spatial properties of relay cells in the lateral geniculate nucleus. J. Neurophysiol. 109, 889–899 (2013).

    PubMed  Google Scholar 

  50. McCarren, M. & Alger, B.E. Use-dependent depression of IPSPs in rat hippocampal pyramidal cells in vitro. J. Neurophysiol. 53, 557–571 (1985).

    CAS  PubMed  Google Scholar 

  51. Thompson, S.M. & Gahwiler, B.H. Activity-dependent disinhibition. II. Effects of extracellular potassium, furosemide and membrane potential on ECl- in hippocampal CA3 neurons. J. Neurophysiol. 61, 512–523 (1989).

    CAS  PubMed  Google Scholar 

  52. Thompson, S.M. & Gahwiler, B.H. Activity-dependent disinhibition. I. Repetitive stimulation reduces IPSP driving force and conductance in the hippocampus in vitro. J. Neurophysiol. 61, 501–511 (1989).

    CAS  PubMed  Google Scholar 

  53. Thompson, S.M. & Gahwiler, B.H. Activity-dependent disinhibition. III. Desensitization and GABAB receptor-mediated presynaptic inhibition in the hippocampus in vitro. J. Neurophysiol. 61, 524–533 (1989).

    CAS  PubMed  Google Scholar 

  54. Willow, M., Gonoi, T. & Catterall, W.A. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol. Pharmacol. 27, 549–558 (1985).

    CAS  PubMed  Google Scholar 

  55. Yaari, Y., Selzer, M.E. & Pincus, J.H. Phenytoin: mechanisms of its anticonvulsant action. Ann. Neurol. 20, 171–184 (1986).

    CAS  PubMed  Google Scholar 

  56. Cheung, H., Kamp, D. & Harris, E. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res. 13, 107–112 (1992).

    CAS  PubMed  Google Scholar 

  57. Pothmann, L. et al. Function of inhibitory micronetworks is spared by Na+ channel–acting anticonvulsant drugs. J. Neurosci. 34, 9720–9735 (2014).

    PubMed  PubMed Central  Google Scholar 

  58. Kawaguchi, Y. & Kubota, Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486 (1997).

    CAS  PubMed  Google Scholar 

  59. Fino, E. & Yuste, R. Dense inhibitory connectivity in neocortex. Neuron 69, 1188–1203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kapfer, C., Glickfeld, L.L., Atallah, B.V. & Scanziani, M. Supralinear increase of recurrent inhibition during sparse activity in the somatosensory cortex. Nat. Neurosci. 10, 743–753 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Pouille, F. & Scanziani, M. Routing of spike series by dynamic circuits in the hippocampus. Nature 429, 717–723 (2004).

    CAS  PubMed  Google Scholar 

  62. Silberberg, G. & Markram, H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 53, 735–746 (2007).

    CAS  PubMed  Google Scholar 

  63. Cobos, I. et al. Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat. Neurosci. 8, 1059–1068 (2005).

    CAS  PubMed  Google Scholar 

  64. Zhu, Y., Stornetta, R.L. & Zhu, J.J. Chandelier cells control excessive cortical excitation: characteristics of whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal neurons. J. Neurosci. 24, 5101–5108 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, Y., Toprani, S., Tang, Y., Vrabec, T. & Durand, D.M. Mechanism of highly synchronized bilateral hippocampal activity. Exp. Neurol. 251, 101–111 (2014).

    CAS  PubMed  Google Scholar 

  66. Woodruff, A.R. et al. State-dependent function of neocortical chandelier cells. J. Neurosci. 31, 17872–17886 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Szabadics, J. et al. Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 311, 233–235 (2006).

    CAS  PubMed  Google Scholar 

  68. Huguenard, J.R. & McCormick, D.A. Thalamic synchrony and dynamic regulation of global forebrain oscillations. Trends Neurosci. 30, 350–356 (2007).

    CAS  PubMed  Google Scholar 

  69. Sohal, V.S., Keist, R., Rudolph, U. & Huguenard, J.R. Dynamic GABA(A) receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. J. Neurosci. 23, 3649–3657 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Sohal, V.S., Pangratz-Fuehrer, S., Rudolph, U. & Huguenard, J.R. Intrinsic and synaptic dynamics interact to generate emergent patterns of rhythmic bursting in thalamocortical neurons. J. Neurosci. 26, 4247–4255 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Skardoutsou, A., Voudris, K.A. & Vagiakou, E.A. Non-convulsive status epilepticus associated with tiagabine therapy in children. Seizure 12, 599–601 (2003).

    PubMed  Google Scholar 

  72. Oláh, S. et al. Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461, 1278–1281 (2009).

    PubMed  PubMed Central  Google Scholar 

  73. Pfeffer, C.K., Xue, M., He, M., Huang, Z.J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Tamás, G., Buhl, E.H. & Somogyi, P. Massive autaptic self-innervation of GABAergic neurons in cat visual cortex. J. Neurosci. 17, 6352–6364 (1997).

    PubMed  PubMed Central  Google Scholar 

  75. Bacci, A., Huguenard, J.R. & Prince, D.A. Functional autaptic neurotransmission in fast-spiking interneurons: a novel form of feedback inhibition in the neocortex. J. Neurosci. 23, 859–866 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Galarreta, M. & Hestrin, S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75 (1999).

    CAS  PubMed  Google Scholar 

  77. Gibson, J.R., Beierlein, M. & Connors, B.W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999).

    CAS  PubMed  Google Scholar 

  78. Letzkus, J.J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480, 331–335 (2011).

    CAS  PubMed  Google Scholar 

  79. Pi, H.J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Jiang, X., Wang, G., Lee, A.J., Stornetta, R.L. & Zhu, J.J. The organization of two new cortical interneuronal circuits. Nat. Neurosci. 16, 210–218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Whittington, M.A., Traub, R.D. & Jefferys, J.G. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373, 612–615 (1995).

    CAS  PubMed  Google Scholar 

  82. Grasse, D.W., Karunakaran, S. & Moxon, K.A. Neuronal synchrony and the transition to spontaneous seizures. Exp. Neurol. 248, 72–84 (2013).

    PubMed  Google Scholar 

  83. Deleuze, C. & Huguenard, J.R. Distinct electrical and chemical connectivity maps in the thalamic reticular nucleus: potential roles in synchronization and sensation. J. Neurosci. 26, 8633–8645 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Landisman, C.E. et al. Electrical synapses in the thalamic reticular nucleus. J. Neurosci. 22, 1002–1009 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, S.J., Huguenard, J.R. & Prince, D.A. GABAA receptor–mediated Cl- currents in rat thalamic reticular and relay neurons. J. Neurophysiol. 78, 2280–2286 (1997).

    CAS  PubMed  Google Scholar 

  86. Sohal, V.S. & Huguenard, J.R. Inhibitory interconnections control burst pattern and emergent network synchrony in reticular thalamus. J. Neurosci. 23, 8978–8988 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Huntsman, M.M., Porcello, D.M., Homanics, G.E., DeLorey, T.M. & Huguenard, J.R. Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science 283, 541–543 (1999).

    CAS  PubMed  Google Scholar 

  88. Huguenard, J.R. & Prince, D.A. Clonazepam suppresses GABAB-mediated inhibition in thalamic relay neurons through effects in nucleus reticularis. J. Neurophysiol. 71, 2576–2581 (1994).

    CAS  PubMed  Google Scholar 

  89. Callaway, E.M. & Katz, L.C. Photostimulation using caged glutamate reveals functional circuitry in living brain slices. Proc. Natl. Acad. Sci. USA 90, 7661–7665 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wuarin, J.P. & Dudek, F.E. Excitatory synaptic input to granule cells increases with time after kainate treatment. J. Neurophysiol. 85, 1067–1077 (2001).

    CAS  PubMed  Google Scholar 

  91. Zhang, W., Huguenard, J.R. & Buckmaster, P.S. Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy. J. Neurosci. 32, 1183–1196 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Morgan, R.J. & Soltesz, I. Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures. Proc. Natl. Acad. Sci. USA 105, 6179–6184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jin, X., Prince, D.A. & Huguenard, J.R. Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epileptogenic neocortex in rats. J. Neurosci. 26, 4891–4900 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Brill, J. & Huguenard, J.R. Enhanced infragranular and supragranular synaptic input onto layer 5 pyramidal neurons in a rat model of cortical dysplasia. Cereb. Cortex 20, 2926–2938 (2010).

    PubMed  PubMed Central  Google Scholar 

  95. Jacobson, S. & Trojanowski, J.Q. The cells of origin of the corpus callosum in rat, cat and rhesus monkey. Brain Res. 74, 149–155 (1974).

    CAS  PubMed  Google Scholar 

  96. Wilson, D.H., Culver, C., Waddington, M. & Gazzaniga, M. Disconnection of the cerebral hemispheres. An alternative to hemispherectomy for the control of intractable seizures. Neurology 25, 1149–1153 (1975).

    CAS  PubMed  Google Scholar 

  97. Caputi, A., Melzer, S., Michael, M. & Monyer, H. The long and short of GABAergic neurons. Curr. Opin. Neurobiol. 23, 179–186 (2013).

    CAS  PubMed  Google Scholar 

  98. Niell, C.M. & Stryker, M.P. Modulation of visual responses by behavioral state in mouse visual cortex. Neuron 65, 472–479 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 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  Google Scholar 

  100. 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  Google Scholar 

  101. 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. Eneuro published online, doi:10.1523/eneuro.0005-14.2014 (1 December 2014).

  102. Iadarola, M.J. & Gale, K. Substantia nigra: site of anticonvulsant activity mediated by gamma-aminobutyric acid. Science 218, 1237–1240 (1982).

    CAS  PubMed  Google Scholar 

  103. Gradinaru, V., Mogri, M., Thompson, K.R., Henderson, J.M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Paz, J.T., Chavez, M., Saillet, S., Deniau, J.M. & Charpier, S. Activity of ventral medial thalamic neurons during absence seizures and modulation of cortical paroxysms by the nigrothalamic pathway. J. Neurosci. 27, 929–941 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Danober, L., Deransart, C., Depaulis, A., Vergnes, M. & Marescaux, C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog. Neurobiol. 55, 27–57 (1998).

    CAS  PubMed  Google Scholar 

  106. Vercueil, L. et al. High-frequency stimulation of the subthalamic nucleus suppresses absence seizures in the rat: comparison with neurotoxic lesions. Epilepsy Res. 31, 39–46 (1998).

    CAS  PubMed  Google Scholar 

  107. Hoffman, S.N., Salin, P.A. & Prince, D.A. Chronic neocortical epileptogenesis in vitro. J. Neurophysiol. 71, 1762–1773 (1994).

    CAS  PubMed  Google Scholar 

  108. Polack, P.O. et al. Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures. J. Neurosci. 27, 6590–6599 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank C. Makinson for critical comments. This work is supported by the US National Institutes of Health and the National Institute of Neurological Disorders and Stroke, and Citizens United Against Epilepsy.

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Paz, J., Huguenard, J. Microcircuits and their interactions in epilepsy: is the focus out of focus?. Nat Neurosci 18, 351–359 (2015). https://doi.org/10.1038/nn.3950

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