Excitatory and inhibitory synapses form a tight subcellular balance along dendrites that decorrelates over development

Abstract

SummaryA balance between excitation and inhibition is crucial for neurotypical brain function. Indeed, disruptions in this relationship are frequently associated with the pathophysiology of neurodevelopmental disorders. Nevertheless, how this balance is established during the dynamic period of neurodevelopment remains unexplored. Using multiple techniques, includingin uteroelectroporation, electron microscopy and electrophysiology, we reveal a tight correlation in the distribution of excitatory and inhibitory synapses along dendrites of developing CA1 hippocampal neurons. This balance was present within short dendritic stretches (<20µm), and surprisingly, was most pronounced during early development, sharply declining with maturity. The tight matching between excitation and inhibition was unexpected, as inhibitory synapses lacked an active zone when formed and exhibited compromised evoked release. We propose that inhibitory synapses form as a stabilising scaffold, to counterbalance growing excitation levels. This relationship diminishes over time, suggesting a critical role for a subcellular balance in early neuronal function and circuit formation.