The Contribution of Raised Intraneuronal Chloride to Epileptic Network Activity

被引:87
作者
Alfonsa, Hannah [1 ]
Merricks, Edward M. [1 ]
Codadu, Neela K. [1 ]
Cunningham, Mark O. [1 ]
Deisseroth, Karl [2 ,3 ,4 ]
Racca, Claudia [1 ]
Trevelyan, Andrew J. [1 ]
机构
[1] Sch Med, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA
[3] Stanford Univ, Dept Psychiat, Stanford, CA 94305 USA
[4] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
基金
英国惠康基金; 英国医学研究理事会;
关键词
chloride; fast spiking interneuron; high frequency oscillations; neocortex; pyramidal neuron; seizure; HIGH-FREQUENCY OSCILLATIONS; ACTIVITY-DEPENDENT DISINHIBITION; FAST RIPPLES; GABAERGIC INHIBITION; NEURONAL-ACTIVITY; HIPPOCAMPUS; SYNCHRONIZATION; MECHANISMS; PROPAGATION; DESYNCHRONIZATION;
D O I
10.1523/JNEUROSCI.4105-14.2015
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Altered inhibitory function is an important facet of epileptic pathology. A key concept is that GABAergic activity can become excitatory if intraneuronal chloride rises. However, it has proved difficult to separate the role of raised chloride from other contributory factors in complex network phenomena, such as epileptic pathology. Therefore, we asked what patterns of activity are associated with chloride dysregulation by making novel use of Halorhodopsin to load clusters of mouse pyramidal cells artificially with Cl-. Brief (1-10 s) activation of Halorhodopsin caused substantial positive shifts in the GABAergic reversal potential that were proportional to the charge transfer during the illumination and in adult neocortical pyramidal neurons decayed with a time constant of tau = 8.0 +/- 2.8s. At the network level, these positive shifts in E-GABA produced a transient rise in network excitability, with many distinctive features of epileptic foci, including high-frequency oscillations with evidence of out-of-phase firing (Ibarz et al., 2010). We show how such firing patterns can arise from quite small shifts in the mean intracellular Cl-level, within heterogeneous neuronal populations. Notably, however, chloride loading by itself did not trigger full ictal events, even with additional electrical stimulation to the underlying white matter. In contrast, when performed in combination with low, subepileptic levels of 4-aminopyridine, Halorhodopsin activation rapidly induced full ictal activity. These results suggest that chloride loading has at most an adjunctive role in ictogenesis. Our simulations also show how chloride loading can affect the jitter of action potential timing associated with imminent recruitment to an ictal event (Netoff and Schiff, 2002).
引用
收藏
页码:7715 / 7726
页数:12
相关论文
共 54 条
[1]   GABA-MEDIATED BIPHASIC INHIBITORY RESPONSES IN HIPPOCAMPUS [J].
ALGER, BE ;
NICOLL, RA .
NATURE, 1979, 281 (5729) :315-317
[2]   What is GABAergic inhibition? How is it modified in epilepsy? [J].
Bernard, C ;
Cossart, R ;
Hirsch, JC ;
Esclapez, M ;
Ben-Ari, Y .
EPILEPSIA, 2000, 41 :S90-S95
[3]   Interictal high-frequency oscillations (80-500Hz) in the human epileptic brain: Entorhinal cortex [J].
Bragin, A ;
Wilson, CL ;
Staba, RJ ;
Reddick, M ;
Fried, I ;
Engel, J .
ANNALS OF NEUROLOGY, 2002, 52 (04) :407-415
[4]   Local generation of fast ripples in epileptic brain [J].
Bragin, A ;
Mody, I ;
Wilson, CL ;
Engel, J .
JOURNAL OF NEUROSCIENCE, 2002, 22 (05) :2012-2021
[5]   Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy [J].
Cammarota, Mario ;
Losi, Gabriele ;
Chiavegato, Angela ;
Zonta, Micaela ;
Carmignoto, Giorgio .
JOURNAL OF PHYSIOLOGY-LONDON, 2013, 591 (04) :807-822
[6]   High-performance genetically targetable optical neural silencing by light-driven proton pumps [J].
Chow, Brian Y. ;
Han, Xue ;
Dobry, Allison S. ;
Qian, Xiaofeng ;
Chuong, Amy S. ;
Li, Mingjie ;
Henninger, Michael A. ;
Belfort, Gabriel M. ;
Lin, Yingxi ;
Monahan, Patrick E. ;
Boyden, Edward S. .
NATURE, 2010, 463 (7277) :98-102
[7]   SYNCHRONIZATION OF NEURONAL-ACTIVITY IN HIPPOCAMPUS BY INDIVIDUAL GABAERGIC INTERNEURONS [J].
COBB, SR ;
BUHL, EH ;
HALASY, K ;
PAULSEN, O ;
SOMOGYI, P .
NATURE, 1995, 378 (6552) :75-78
[8]   On the origin of interictal activity in human temporal lobe epilepsy in vitro [J].
Cohen, I ;
Navarro, V ;
Clemenceau, S ;
Baulac, M ;
Miles, R .
SCIENCE, 2002, 298 (5597) :1418-1421
[9]   Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies [J].
Cossart, R ;
Bernard, C ;
Ben-Ari, Y .
TRENDS IN NEUROSCIENCES, 2005, 28 (02) :108-115
[10]   Fluctuating synaptic conductances recreate in vivo-like activity in neocortical neurons [J].
Destexhe, A ;
Rudolph, M ;
Fellous, JM ;
Sejnowski, TJ .
NEUROSCIENCE, 2001, 107 (01) :13-24