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Cortical processing in sensory perception requires the integration of sensory (bottom-up) input with internally generated contextual (top-down) information. Top-down inputs reach layer 1 (L1), the outermost layer of the neocortex.

Additional to top-down projection fibers, L1 contains GABAergic inhibitory interneurons (INs) embedded in a mesh of pyramidal neuron (PN) dendrites. L1 INs provide dendritic inhibition along the cortical column, modulating incoming Top-Down inputs. However, it is currently poorly understood which mechanisms contribute to integrate contextual information in L1.

A large population (70%) of L1 INs expresses Neuron-derived neurotrophic factor (NDNF), which is used as a genetic handle to target cortical L1 INs. Surprisingly, we found a large fraction (~70%) of L1 INs of the mouse primary visual cortex (V1) expresses the cannabinoid receptor type 1 (CB1) and colocalizes with NDNF. Since CB1 receptors mediate suppression of presynaptic release through retrograde endocannabinoid signaling, we hypothesize that CB1-mediated modulation is a mechanism involved in Top-down integration in L1.

 To understand better which L1 IN cell types express CB1, we examined the electrophysiological and morphological features of L1 INs in V1.  In acute brain slices of a mouseline that expresses the cytosolic fluorescent marker tdTomato under the CB1-promotor, we performed whole-cell patch clamp of L1 INs. CB1 expressing L1 INs do not identify a specific morpho-functional IN subtype, as they exhibit a wide range of properties.

To assess the modulation by endocannabinoids in L1, we tested CB1-mediated plasticity at the synapse between NDNF L1 INs L2/3 PNs. Through Channelrhodopsin2 expression in NDNF INs and whole-cell patch clamp recordings in L2/3 PNs, we show that CB1-mediated plasticity is present between L1-NDNF INs and L2/3 PNs.  Therefore, we found functional CB1-mediated plasticity at an unexpected cortical GABAergic synapse.

Using in vivo 2-photon imaging, we investigate how CB1 in L1 affects the integration of Top-down inputs during visual stimulation.

Altogether, this may serve as a pivotal mechanism to gate top-down inputs onto PNs during visual processing.