LTP OF EXCITATORY INPUTS TO VIP-INS IN THE LAYER 2/3 BARREL CORTEX RELIES ON RETROGRADE SIGNALING BY ENDOCANNABINOIDS

Synaptic plasticity is a crucial phenomenon for learning process. Long-term potentiation (LTP) is a widely recognized cellular model used to study plastic changes of synaptic transmission. Here, we dissected mechanisms of LTP occurring at excitatory connections to vasoactive intestinal polypeptide-expressing interneurons (VIP-INs), one of three major GABAergic interneuron classes. VIP-INs provide a disinhibitory loop to local excitatory neurons via inhibition of other interneurons.
We used patch-clamp technique in acute brain slices of transgenic mice expressing Td-Tomato in VIP-INs. Excitatory postsynaptic currents (EPSC) were evoked in layer 2/3 VIP-INs of the somatosensory cortex using neighboring extracellular stimulation. To evoke LTP, we applied a protocol of pairing presynaptic electrical stimulation with postsynaptic membrane depolarization. Using pharmacological tools, we established that LTP of glutamatergic inputs onto VIP-INs is NMDAR- and mGluR-5-independent. However, LTP was mediated by mGluR-1 and L-type voltage gated calcium channels. Moreover, mGluR-1 acted through Src-family signaling, without involvement of transient receptor potential channels (TRPC). Analyses of paired-pulse ratio and coefficient of variation suggested that LTP is expressed presynaptically. Looking for retrograde signaling pathways involved in expression of LTP, we found that postsynaptically synthesized endocannabinoids (eCBs) but not brain-derived neurotrophic factor (BDNF) might be responsible for presynaptic expression of LTP at excitatory synapses on layer 2/3 VIP-INs.
In conclusion, our study broadens our knowledge in LTP mechanisms, and shows eCBs as unusual retrograde messengers involved in LTP.
This study was supported by the National Science Centre (Poland), OPUS grant no. 2020/39/B/NZ4/01462 to JUC.