GABAergic inhibition shapes interictal dynamics in awake epileptic mice.
Epilepsy is characterized by recurrent seizures and brief, synchronous bursts called interictal spikes that are present in-between seizures and observed as transient events in EEG signals. While GABAergic transmission is known to play an important role in shaping healthy brain activity, the role of inhibition in these pathological epileptic dynamics remains unclear. Examining the microcircuits that participate in interictal spikes is thus an important first step towards addressing this issue, as the function of these transient synchronizations in either promoting or prohibiting seizures is currently under debate. To identify the microcircuits recruited in spontaneous interictal spikes in the absence of any proconvulsive drug or anaesthetic agent, we combine a chronic model of epilepsy with in vivo two-photon calcium imaging and multiunit extracellular recordings to map cellular recruitment within large populations of CA1 neurons in mice free to run on a self-paced treadmill. We show that GABAergic neurons, as opposed to their glutamatergic counterparts, are preferentially recruited during spontaneous interictal activity in the CA1 region of the epileptic mouse hippocampus. Although the specific cellular dynamics of interictal spikes are found to be highly variable, they are consistently associated with the activation of GABAergic neurons, resulting in a perisomatic inhibitory restraint that reduces neuronal spiking in the principal cell layer. Given the role of GABAergic neurons in shaping brain activity during normal cognitive function, their aberrant unbalanced recruitment during these transient events could have important downstream effects with clinical implications.
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
Sarah Feldt
SF
Muldoon
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
Vincent
V
Villette
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
Thomas
T
Tressard
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
Arnaud
A
Malvache
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France.
Susanne
S
Reichinnek
4 Institut des Neurosciences des Systèmes, Institut National de la Santé et de la Recherche Médicale Unité 1106, 13005 Marseille, France.
Fabrice
F
Bartolomei
1 Institut National de la Santé et de la Recherche Médicale Unité 901, 13009 Marseille, France 2 Aix-Marseille Université, Unité Mixte de Recherche S901, 13009 Marseille, France 3 Institut de Neurobiologie de la Méditerranée, 13009 Marseille, France rosa.cossart@inserm.fr.
Rosa
R
Cossart
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000473:pathology*; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D016014:Linear Models; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018721:Muscarinic Agonists / Q000633:toxicity; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010862:Pilocarpine / Q000633:toxicity; D014851:Wakefulness
D002147:Calmodulin; D018721:Muscarinic Agonists; D010862:Pilocarpine; D049452:Green Fluorescent Proteins; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D002118:Calcium
GABA; calcium imaging; epilepsy; interictal spikes; microcircuits