CB1-MEDIATED PLASTICITY OF A DISINHIBITORY CORTICAL CIRCUIT ENABLES FLEXIBLE VISUAL COMPUTATIONS IN MOUSE V1

Visual perception is shaped by cortical interneurons (INs) across behavioral contexts and internal states, enabling flexible cortical computations. Endocannabinoids strongly depress GABAergic inhibition acting retrogradely via cannabinoid receptor type 1 (CB1). CB1 expression is prominent in perisomatic cholecystokinin-positive INs, but CB1 signaling across different INs remains poorly understood. We have found that a large proportion of the vasoactive intestinal peptide (VIP) INs express CB1. VIP INs specialize in inhibiting somatostatin (SST)-positive INs, forming a disinhibitory motif that sculpts excitatory neuron activity and contributes to visual processing, including spontaneous activity, surround suppression and figure–ground perception. Here, we used whole-cell patch-clamp recordings and optogenetics and we found strong CB1–dependent plasticity at VIP–SST synapses in layer 2/3 of the mouse primary visual cortex (V1). We then investigated whether this undescribed endocannabinoid-mediated plasticity at IN-IN synapses dynamically regulates visual computations. In vivo two-photon calcium imaging experiments in V1 revealed that CB1 receptors in VIP INs facilitate both surround suppression and figure–ground perception. Consistently, mice lacking CB1 in VIP INs (VIP-CB1-KO) show deficits in visual depth perception and visually evoked innate defensive behaviors, such as freezing in response to sweeping overhead stimuli. Altogether, these findings identify CB1 signaling in VIP INs as a key mechanism supporting flexible cortical inhibition and visual perception, with potential relevance for neurodevelopmental disorders involving altered inhibitory circuit function.