And a very special shout out to my co-first author Paul Philipsberg. He doesn’t internet, but he’s a phenomenal grad student in the lab and the literal wizard behind PhaSER. If you use PhaSER (github.com/ShumanLab/Ph...), you have him to thank!

And it all couldn’t have happened without the incredible team of people that worked on this over the last 6 years. Words cannot convey how amazing a group this is.

@susieyufeng.bsky.social @laurenmvetere.bsky.social @denisejcai.bsky.social @tristanshuman.bsky.social

Finally, we tested if altered PV+ phase locking was sufficient to induce seizure susceptibility in otherwise healthy animals, by shifting PV+ spiking to the peak of theta… And it was!

Then we applied this manipulation to test if, in epilepsy, restoring PV+ interneuron spiking to the trough of theta could reduce seizure susceptibility. It did!

(This is the part of the paper where I had to summarize many. many. many. years of work in 2 sentences):

PhaSER works best to shift the phase locking of interneurons when coupled with bidirectional manipulations (thank you, BiPOLES!!!) 👏 @simwieg.bsky.social @johvierock.bsky.social

Now, there’s a long list of disorders with altered phase locking. But finding the causal role of this change in spike timing was impossible due to limitations in technology.

Enter, 〰️PhaSER 〰️: a closed-loop system that delivers phase-locked manipulations to ongoing oscillations.

.@tristanshuman.bsky.social and @susieyufeng.bsky.social previously showed that DG interneurons have dramatically altered theta phase locking in epilepsy. Not only did we replicate this (2x!), we found that PV+ interneurons specifically showed theta phase locking deficits in epilepsy.

But let’s start from the beginning.

First: phase locking profiles in dentate PV+ and SOM+ cells in healthy mice. PV+ cells were highly coupled to the theta trough while SOM+ interneurons showed more widely distributed spiking. (I think this is really cool and I have theories...)

🚨New preprint alert🚨
We used closed-loop optogenetics to causally test the importance of inhibitory spike timing in network function and found that manipulating PV+ cell theta phase locking in the dentate gyrus can shift seizure susceptibility (both ways!)

I can't emphasize enough how incredible this community of Simons fellows is! The retreat earlier this summer was massively energizing and inspiring. Such an honor to be a part of this group. Can't wait for next year!

Photos: DeShaun Craddock and Emily Tan for Simons Foundation