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Inhibitory synapses provide scaffold to balance growing excitation during early development


Harmony between excitatory and inhibitory signalling is crucial for healthy brain function, and its disruption is implicated in many neurological and psychiatric disorders. To understand how this balance forms during brain development, Sally Horton (first author), colleagues in the Burrone lab, Robert Hindges, and collaborators from the CUI and Universidade do Porto, set out to comprehensively map all the synaptic connections (both excitatory and inhibitory) coming onto single dendritic branches within a specific region of the mouse brain.

Horton et al. used three independent methods for monitoring synaptic structure and function: genetically encoded synaptic binding proteins, serial block-face scanning electron microscopy and electrophysiological recording of locally evoked synaptic currents (Figure). These measurements revealed a significant, yet not very precise match between inhibitory and excitatory inputs at the level of individual dendritic domains, as small as 20 micrometers.

The surprise came when they studied how this excitation-inhibition balance evolved during development. The strongest correlation between the distribution of excitatory and inhibitory synapses was found shortly after their formation during early development. These observations suggest a coordinated mechanism for the building of these connections. Intriguingly, early inhibitory synapses, despite their very precise placement, displayed immature characteristics in both their molecular makeup and their ability to respond to stimulation.

Taken together, these results suggest that inhibitory synapses initially act like a support structure, balancing the increasing excitatory activity during early brain development. This early, tight coordination between excitation and inhibition weakens over time, implying a crucial role for this subcellular balance in establishing proper neuronal function and brain circuitry.

By Guilherme Neves, co-corresponding author