New Research Identifies Key Molecules for Brain Synapse Formation

New research has identified two specific molecules crucial for the formation of synapses between inhibitory interneurons and their target excitatory neurons in the brain. These synapses are vital structures that transmit signals between neural partners.These inhibitory interneurons are responsible for coordinating communication in the brain, regulating information processing, and maintaining proper balance within brain circuits by controlling the activity of excitatory neurons. Disruptions in coordination between these cell types can lead to circuit malfunction, which is associated with conditions such as epilepsy, depression, autism, and schizophrenia.The research team determined that the presence of two distinct proteins in precise locations on each cell facilitates a "handshake" process, known as innervation. This process generates synapses on the excitatory neurons, establishing a lasting communication channel between the two cell types.According to first author Yasufumi Hayano, these inhibitory interneurons shape and balance local circuit activity, acting as modulators and coordinators. The study concluded that the interaction between these two specific proteins regulates the specificity of synapse formation. Hayano noted that if this process is disrupted, it could have implications for neuronal disorders, a possibility that warrants further investigation.The study was published online in the Journal of Neuroscience. Senior study author Hiroki Taniguchi's neurobiology research program at The Ohio State University College of Medicine focuses on cortical circuitry development to identify potential therapeutic targets for neuronal disorders.This study specifically examined chandelier cells, a type of inhibitory interneuron in the brain's cortex, known for their distinctive spray of synapses that allow them to control hundreds of cells simultaneously. Chandelier cells coordinate the activity of excitatory pyramidal neurons in the cortex, and their synaptic reduction has been linked to brain disorders like schizophrenia and epilepsy. The precise mechanisms of their association were not fully understood prior to this research.Previous research indicated that these cells connect through synapse specificity at a precise junction point, likely facilitated by cell adhesion molecules. The connection to excitatory pyramidal cells occurs at the axon initial segment, a region close to where an axon extends from the cell body. As the axon initial segment generates neuronal signals (action potentials) for communication, chandelier cells are considered highly influential in regulating activity patterns within excitatory neuron networks.Hayano described the axon initial segment as a "faucet" that releases information, with chandelier cells controlling this faucet to prevent pyramidal neurons from transmitting information to other neurons.Through RNA sequencing analysis, the team identified gliomedin as a cell surface molecule enriched in chandelier cells. Gliomedin is a known receptor for neurofascin-186, which is localized in the axon initial segment.Visualizations using dyes in the brains of young mice confirmed this connection, showing that chandelier cells formed synapses (cartridges) on the axon initial segments of pyramidal neurons. Experiments involving the deletion or overexpression of the genes responsible for these two proteins demonstrated a reduction in synapse formation when the genes were absent and an increase when they were highly expressed.Hayano stated that gliomedin in chandelier cells and neurofascin-186 at the axon initial segment are both essential for the development of chandelier synapse formation. This mechanism explains how the brain specifies synapses at tiny segments within its complex structure.The researchers plan to apply similar strategies to explore other types of inhibitory interneurons, particularly those predicted to involve different molecular mechanisms.This work received support from the National Institutes of Health, the Max Planck Society, The Ohio State University Wexner Medical Center, and Ohio State’s Chronic Brain Injury Program. Additional co-authors included Yugo Ishino, Manzoor Bhat, and Elior Peles.