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.
Highlights
Athilingam et al, 2017), our results identify cortical Sst interneurons as novel targets of the 5110 HT neuromodulatory system via 5-HT2A receptor (5-HT2AR)
We found that upstates were present synchronously in the local field potential (LFP) of all the recording channels (Figure 1–figure supplement 1), and that every upstate coincided with large increases in population spiking activity medial, L = lateral, P= posterior, A = anterior)
In this study we show that the substitute amphetamines MDMA and Fen suppress default 310 cortical network oscillations in vivo in the medial entorhinal cortex (mEC)
Summary
5-HT is one of the most important neuromodulators in the central nervous system. Projections 44 originating from the Raphe nuclei, the brain-stem structure that comprises the majority of 545 HT releasing neurons in the brain, innervate all cortical and sub-cortical areas (Descarries et al., 2010). 5-HT levels in the brain are closely linked to the sleep-wake cycle : the activity of serotonergic raphe neurons is increased during wakefulness, decreased during slow-wave sleep (SWS) and virtually silent during REM sleep (McGinty and Harper, 1976, Oikonomou et al., 2019, Unger et al, 2020). On the other hand, blocking ACh and 5-HT transmission at the same time causes a continuous “synchronized” cortical state, even during active behavior, suggesting that 5-HT plays an important role in mediating transitions between different network states (Vanderwolf and Baker, 1986). In agreement with this line of thought, electrical and optogenetic stimulation of the Raphe nuclei reduce low frequency (1-10 Hz) power in the cortex, implying a reduction in neuronal synchronization at these frequencies (Puig et al, 2010, Grandjean et al, 2019). While previous studies have shown that parvalbumin (PV) interneurons are excited by 5-HT2AR (Puig et al, 2010, Athilingam et al, 2017), our results identify cortical Sst interneurons as novel targets of the 5110 HT neuromodulatory system via 5-HT2AR
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