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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.

In this Technical Report, Chuong and colleagues introduce Jaws, an archaeon-derived, photoactivatable chloride pump that responds to red light. Owing to its efficiency in absorbing red photons and its large photocurrent, Jaws can be transcranially activated deep in the brain and thus allows noninvasive optogenetic silencing. Optogenetic inhibition of the electrical activity of neurons enables the causal assessment of their contributions to brain functions. Red light penetrates deeper into tissue than other visible wavelengths. We present a red-shifted cruxhalorhodopsin, Jaws, derived from Haloarcula ( Halobacterium ) salinarum (strain Shark) and engineered to result in red light–induced photocurrents three times those of earlier silencers. Jaws exhibits robust inhibition of sensory-evoked neural activity in the cortex and results in strong light responses when used in retinas of retinitis pigmentosa model mice. We also demonstrate that Jaws can noninvasively mediate transcranial optical inhibition of neurons deep in the brains of awake mice. The noninvasive optogenetic inhibition opened up by Jaws enables a variety of important neuroscience experiments and offers a powerful general-use chloride pump for basic and applied neuroscience.

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 two identified hippocampal interneuron classes during seizure induction in vivo. We identified cell type-specific differences in preictal firing patterns and input sensitivity of parvalbumin- and somatostatin-expressing interneurons. Surprisingly, the impact of both sources of inhibition remained intact throughout the preictal period and into the early ictal phase. Our findings suggest that the onset of ictal activity is not due to a failure of inhibition, but is instead associated with a decoupling of inhibitory cells from their normal relationship with the local hippocampal network.