Serotonin-endocannabinoid crosstalk selectively regulates inhibitory GABAergic inputs in the medial prefrontal cortex

Abstract Serotonin (5-HT) plays an important role in shaping brain network dynamics by regulating excitatory synaptic function and neuronal excitability. However, much less is known about how 5-HT tunes synaptic inhibition. Here, we demonstrate that transient 5-HT signaling persistently suppresses GABAergic synapses onto layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC). Moreover, we found that 5-HT1A and 5-HT2A receptors differentially contribute to 5-HT regulation of synaptic inhibition, possibly by acting at distinct GABAergic cell subpopulations. Importantly, 5-HT2A receptor activation triggers retrograde endocannabinoid signaling to reduce GABA release selectively at synapses formed by somatostatin (SST+)- but not parvalbumin (PV+)-positive GABAergic interneurons. Altogether, our results highlight the diverse molecular and cell-type-specific mechanisms by which 5-HT signaling modulates inhibitory circuits to shape cortical function.