title: The contribution of raised intraneuronal chloride to epileptic network activity.
abstract: 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 τ = 8.0 ± 2.8s. At the network level, these positive shifts in EGABA 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).
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Alfonsa
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and.
authors.forename: Edward M
authors.identifier: http://orcid.org/0000-0001-8172-3152
authors.initials: EM
authors.lastname: Merricks
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and.
authors.forename: Neela K
authors.initials: NK
authors.lastname: Codadu
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Cunningham
authors.affiliation: Departments of Bioengineering and Psychiatry and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Racca
authors.affiliation: Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and andrew.trevelyan@ncl.ac.uk.
authors.forename: Andrew J
authors.identifier: http://orcid.org/0000-0001-9307-4241
authors.initials: AJ
authors.lastname: Trevelyan
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism / Q000494:pharmacology*; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D005110:Extracellular Space / Q000378:metabolism; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D025602:Halorhodopsins / Q000378:metabolism; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats
chemical_list: D002712:Chlorides; D025602:Halorhodopsins; D026902:Potassium Channel Blockers; D015761:4-Aminopyridine
keywords: chloride; fast spiking interneuron; high frequency oscillations; neocortex; pyramidal neuron; seizure