Abstracts

Network-wide oscillations, such as theta, orchestrate and organize the spiking of individual neurons. This leads many neurons, particularly interneurons, to be active at specific phases of ongoing oscillations, a phenomenon known as phase locking. This precise temporal organization of spiking is thought to be critically important for maintaining excitatory-inhibitory homeostasis and network function broadly. Indeed, theta phase locking of inhibitory neurons in the dentate gyrus is severely disrupted in a mouse model of chronic temporal lobe epilepsy. This strongly suggests that disruptions to theta phase-locked spiking may underly network dysfunction in epilepsy, though the causal influence of this phenomenon has never been determined. Thus, here we directly test the hypothesis that inhibitory theta phase locking can bidirectionally control seizure susceptibility in control and epileptic mice.

To test this hypothesis, we developed a low-latency closed-loop optogenetic system (PhaSER) to bidirectionally control inhibitory phase locking to theta in head-fixed control and pilocarpine-treated epileptic mice navigating a virtual track. Using opto-tagging strategies, we first identified the preferred firing phase of parvalbumin (PV)+ and somatostatin (SOM)+ dentate interneurons. We then applied our closed-loop system to directly control the phase locking of these dentate interneurons to their preferred or non-preferred phase of theta while measuring latency to seize after a systemic kainic acid injection.

In control mice, both PV+ and SOM+ interneurons in the dentate gyrus are primarily active at the trough of CA1 theta oscillations, while in epileptic mice, PV+ interneurons have disrupted phase locking. We found that mis-aligning PV+ interneuron spiking to the peak of theta increased seizure susceptibility in otherwise healthy, control mice and that re-aligning PV+ spiking to the trough of theta diminished seizure susceptibility in epileptic mice. On the other hand, manipulating SOM+ interneuron phase locking did not impact seizure susceptibility in either control or epileptic animals.

These data suggest that theta phase locking of PV+ interneuron spiking plays an important and causal role in seizure susceptibility. Gaining deeper insights into the impacts of inhibitory theta phase locking will reveal the potential of oscillation-driven stimulation as an effective epilepsy therapeutic, and the direct influence that specific interneurons’ theta phase locking holds over network-wide activity.