An unconventional paracrine pathway for the development and maintenance of synaptic inhibition at a central synapse

Optimal mammalian brain function relies on well-organized neuronal networks. GABAergic inhibitory interneurons precisely target subcellular regions to modulate synaptic inhibition and influence the timing of different neural networks. However, the molecular mechanisms guiding the assembly and stability of inhibitory synapses remain largely undefined. In this study, we explored an extracellular signalling pathway that uphold synaptic inhibition at a central inhibitory synapse. Using the cerebellar basket cell to Purkinje cell connection as a model, we discovered an unconventional paracrine pathway crucial to the development and maintenance of synaptic inhibition. Genetic ablation of the key signalling molecule resulted in the disrupted assembly of synaptic protein complexes, perturbed temporal dynamics of Purkinje cell activity, and deficits in motor coordination and learning. Interestingly, restoration of this pathway in adult animals rescues these synaptic and cellular impairments. Consequently, our research has revealed a novel paracrine mechanism that is essential for maintaining synaptic inhibition and neural function in the brain.