Neuronal excitability is permanently altered by activity manipulation during an embryonic critical period in Drosophila

Abstract

Neuronal intrinsic excitability provides the baseline that homeostatic mechanisms act to preserve, yet the processes that establish a baseline remain poorly defined. Developmental critical periods (CPs) are thought to play a central role, but the link between early activity and long-term intrinsic properties is not well characterised. To address this, we used the genetic tractability of the Drosophila larval locomotor circuit to manipulate individual neurons during an embryonic CP. Following optogenetic excitation or inhibition, during the CP, we assessed intrinsic excitability of the same neurons in third-instar larvae (i.e. [~]5 days thereafter). We compared an excitatory premotor interneuron (A27h), an inhibitory premotor interneuron (A31k), and a motor neuron (aCC). Both interneurons exhibited anti-homeostatic responses: excitatory perturbation increased intrinsic excitability, while inhibitory perturbation decreased it, effects that persisted throughout larval development. In contrast, motor neurons showed no significant changes under the same conditions, revealing cell type-specific sensitivity to early activity. These findings build on the general principles of the functional relationships between CP activity and neuronal excitability and how intrinsic excitability is not passively set but actively shaped during these windows, with long-lasting, neuron-specific consequences. More broadly, our results highlight how developmental perturbations can alter the excitatory-inhibitory balance of mature neural circuits that may contribute to the aetiology of neurodevelopmental disorders.