INTRODUCTION: Learning process occurs through synaptic plasticity. Cellular model of synaptic plasticity is called long-term potentiation (LTP), in which specific stimulation of inputs results in long-lasting strengthening of the synaptic transmission. In the present study, we described LTP at excitatory inputs onto layer 2/3 vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory cortex. VIP-INs contribute to one of three main inhibitory neuron classes. However, VIP-INs possess a unique function within the neuronal network, because they promote excitation by targeting and inhibiting other populations of GABAergic cells and thus disinhibiting glutamatergic neurons.

AIM(S): Our study aims to unravel the mechanism of LTP onto cortical VIP-INs.

METHOD(S): We studied fluorescently-labelled VIP-INs in acute brain slices of transgenic mice, utilizing whole-cell patch clamp technique. LTP was evoked with a pairing paradigm, where extracellular stimulation was paired with postsynaptic depolarization of the membrane.

RESULTS: Pharmacological blockage of specific receptors revealed that LTP at excitatory synapses on layer 2/3 VIP-INs is NMDAR- and mGluR-5-independent. In contrast, LTP is controlled by mGluR-1 and L-type voltage-gated calcium channels. Furthermore, Src-family kinase signaling contributes to this process, however without involvement of common pathway through transient receptor potential channels (TRPC). Paired-pulse ratio and coefficient of variation analyses hint toward presynaptic mechanism of LTP expression. Looking for a retrograde messenger that mediates LTP expression, we found that postsynaptically synthesized endocannabinoids, but not brain-derived neurotrophic factor (BDNF), are involved in LTP at VIP-INs.

CONCLUSIONS: Altogether, our study describes for the first time mechanism of LTP at excitatory inputs onto layer 2/3 VIP-INs, showing endocannabinoid signaling as an unconventional retrograde factor in LTP expression.

FINANCIAL SUPPORT: This research was funded by the National Science Centre, Poland, OPUS grant no. 2020/39/B/NZ4/01462 to JUC.