Abstract
Although failure of GABAergic inhibition is a commonly hypothesized mechanism underlying seizure disorders, the series of events that precipitate a rapid shift from healthy to ictal activity remain unclear. Furthermore, the diversity of inhibitory interneuron populations poses a challenge for understanding local circuit interactions during seizure initiation. Using a combined optogenetic and electrophysiological approach, we examined the activity of identified mouse hippocampal interneuron classes during chemoconvulsant seizure induction in vivo. Surprisingly, synaptic inhibition from parvalbumin- (PV) and somatostatin-expressing (SST) interneurons remained intact throughout the preictal period and early ictal phase. However, these two sources of inhibition exhibited cell-type-specific differences in their preictal firing patterns and sensitivity to input. Our findings suggest that the onset of ictal activity is not associated with loss of firing by these interneurons or a failure of synaptic inhibition but is instead linked with disruptions of the respective roles these interneurons play in the hippocampal circuit.
Highlights
Seizure activity is commonly considered to arise from an imbalance of excitation and inhibition in vulnerable neural circuits, leading to unconstrained activity that self-organizes into patterns of hypersynchrony
The transition to ictal activity has been characterized in a variety of ways in rodents, including by manual validation (Henderson et al, 2014), threshold detection of increased EEG power (Khoshkhoo et al, 2017), and combined measurement of EEG power trajectory and spectral features (Krook-Magnuson et al, 2014)
In the current study, where we utilized an acute chemoconvulsant seizure induction, the onset of the ictal period was defined quantitatively by increased local field potentials (LFPs) amplitude, which largely corresponded to the first ictal spike
Summary
Seizure activity is commonly considered to arise from an imbalance of excitation and inhibition in vulnerable neural circuits, leading to unconstrained activity that self-organizes into patterns of hypersynchrony. One mechanism of such an imbalance may be a transient loss of GABAergic inhibition (Ziburkus et al, 2006). Acute blockade of GABA receptors rapidly initiates seizure activity (Rose and Blakemore, 1974; Treiman, 2001), suggesting the necessity of synaptic inhibition to maintain healthy activity patterns. The circuit mechanisms underlying seizure initiation in vivo and the specific role of GABAergic interneurons remain largely unknown
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