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Ruxandra Barzan, Beyza Bozkurt, Mohammadreza Mohagheghi Nejad, Sandra Süß, Tatjana Surdin, Hanna Böke, Katharina Spoida, Zohre Azimi, Michelle Grömmke, Dennis Eickelbeck, Melanie Danelle Mark, Lennard Rohr, Ida Siveke, Sen Cheng, Stefan Herlitze, Dirk Jancke

• Response gain is a crucial means by which modulatory systems control the impact of sensory input. In the visual cortex, the serotonergic \((5-HT_{2A})\) receptor is key in such modulation. However, due to its expression across different cell types and lack of methods that allow for specific activation, the underlying network mechanisms remain unsolved. Here we optogenetically activate endogenous G protein-coupled receptor (GPCR) signaling of a single receptor subtype in distinct \(\it mouse\) neocortical subpopulations in vivo. We show that photoactivation of the \((5-HT_{2A})\) receptor pathway in pyramidal neurons enhances firing of both excitatory neurons and interneurons, whereas \((5-HT_{2A})\) photoactivation in parvalbumin interneurons produces bidirectional effects. Combined photoactivation in both cell types and cortical network modelling demonstrates a conductance-driven polysynaptic mechanism that controls the gain of visual input without affecting ongoing baseline levels. Our study opens avenues to explore GPCRs neuromodulation and its impact on sensory-driven activity and ongoing neuronal dynamics.