Abstracts

Network-wide oscillations, such as theta, orchestrate and organize the spiking of individual neurons in a phenomenon known as phase locking. Phase locking has long been thought to maintain excitatory-inhibitory homeostasis and coordinate cognitive processes. We’ve recently found altered theta phase locking of inhibitory neurons in the dentate gyrus of epileptic mice with spontaneous seizures and cognitive deficits. While phase locking has been widely studied in a variety of contexts using correlational methods, the direct, causal influence of this phenomenon has never been determined. Thus, we aimed to directly test the hypothesis that inhibitory theta phase locking can bidirectionally control seizures and cognitive performance in control and epileptic mice.

To test these hypotheses, we developed a low-latency closed-loop optogenetic system 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 in control and epileptic mice. We then applied our closed-loop system to lock the spiking of these dentate interneurons to their preferred or non-preferred phase of theta while measuring seizure activity and accuracy while navigating a virtual environment.

Using our closed-loop optogenetic system in awake behaving mice, we have validated our ability to precisely alter the phase locking of hippocampal interneurons. Using this system, we have found that mis-aligning inhibitory spiking to the peak of theta increases seizure susceptibility in otherwise healthy, control mice. Furthermore, in epileptic mice, re-aligning inhibitory spiking to the trough of theta diminishes pathological epileptic activity compared to stimulating at the peak of theta. Finally, we have preliminary data demonstrating that precise theta phase locking of dentate gyrus inhibitory neurons influences performance on a demanding dentate-dependent virtual navigation task.

Together, these data suggest that theta phase locking of inhibitory spiking plays an important and causal role in two of the most concerning elements of epilepsy: hyperexcitability and cognitive deficits. Gaining deeper insights into the impacts of inhibitory theta phase locking may reveal the potential of oscillation-driven stimulation as an effective epilepsy therapeutic.