Synapses in the central nervous system are highly specialized structures dedicated to the transfer of information from one neuron to another. Each neuron receives thousands of excitatory and inhibitory synaptic inputs along their dendrites, that are integrated at the axon initial segment (AIS) to generate a new electrical signal called an Action Potential. Regulation of this fundamental process is key for proper brain function and was shown to be altered in several neurodevelopmental pathologies such as schizophrenia and autism spectrum disorder. Interestingly, the AIS of pyramidal neurons (PNs) is innervated by a specific type of inhibitory interneuron, a Chandelier cell. Although these axo-axonic synapses are thought to be capable of tightly regulating AP initiation, their structural and functional properties remain largely unexplored. At classical synapses formed along dendrites, the molecular organisation of synaptic proteins at the nanoscale is a key factor in fine- tuning the efficiency of synaptic transmission. However, the precise nanoscale arrangement of molecules at axo-axonic synapses has not been previously characterised, nor its impact on the modulation of pyramidal neuron firing. Here, we have shown that key proteins such as Gephyrin, the main scaffolding protein of inhibitory synapses, forms subsynaptic domains (SSD) at axo-axonic synapses. These SSDs display different properties, in term of size and density of proteins, when compared to dendritic synapses, which are formed by different types of interneurons. In addition, using genetic tools to chronically increase neuronal activity of PNs in the somatosensory cortex in vivo, we have shown that the nanoscale organisation of gephyrin is plastic. We are currently assessing the functional impact of this intriguing plasticity. Our findings provide a potential mechanism by which Chandelier cells synapse tune their strength to control PN output.
