Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Serotonin (5-HT) is a key neuromodulator in the mammalian brain, but how it affects synchronized cortical network activity is not fully understood. This work shows that MDMA and fenfluramine, two drugs that release 5-HT, inhibit slow oscillations—a default cortical activity pattern—in the entorhinal cortex of anesthetized mice. The suppression occurs through activation of somatostatin-expressing interneurons via the 5-HT2A receptor. Because 5-HT2A receptor signaling is implicated in psychiatric disorders and mediates effects of serotonergic drugs, this link between these interneurons and serotonin may help clarify these complex topics.

Study at a glance

Abstract

Serotonin (5-HT) is one of the major neuromodulators present in the mammalian brain and has been shown to play a role in multiple physiological processes. The mechanisms by which 5-HT modulates cortical network activity, however, are not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SOs), a synchronized cortical network activity universally present across species. SOs are observed during anesthesia and are considered to be the default cortical activity pattern. We discovered that (±)3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine, two potent 5-HT releasers, inhibit SOs within the entorhinal cortex (EC) in anesthetized mice. Combining opto- and pharmacogenetic manipulations with in vitro electrophysiological recordings, we uncovered that somatostatin-expressing (Sst) interneurons activated by the 5-HT2A receptor (5-HT2AR) play an important role in the suppression of SOs. Since 5-HT2AR signaling is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, we propose that the newly discovered link between Sst interneurons and 5-HT will contribute to our understanding of these complex topics.