Balance of Activity during a Critical Period Tunes a Developing Network

Abstract

Developing neural circuits are influenced by activity and are especially sensitive to changes in activity during critical periods (CPs) of development. Changes occurring during a CP often become locked-in so that they affect the mature network. Indeed, several neurodevelopmental disorders have been linked to excessive activity during such periods. It is, therefore, important to identify those aspects of neural circuit development that are influenced by neural activity during a CP. In this study, we take advantage of the genetic tractability of Drosophila to show that activity perturbation during an embryonic CP permanently alters properties of the locomotor circuit. Specific changes we identify include increased synchronicity of motoneuron activity, and greater strengthening of excitatory over inhibitory synaptic drive to motoneurons. These changes are sufficient to reduce network robustness, evidenced by increased sensitivity to induced seizure. We also show that we can rescue these changes when increased activity is mitigated by inhibition provided by mechanosensory neurons. Similarly, we demonstrate a dose-dependent relationship between inhibition experienced during the CP, and the extent to which it is possible to rescue the hyperexcitable phenotype characteristic of the parabss mutation. This suggests that developing circuits must be exposed to a properly balanced sum of excitation and inhibition during the CP, to achieve normal mature network function. Our results, therefore, provide novel insight into how activity during a CP shapes specific elements of a circuit, and how activity during this period is integrated to tune neural circuits to the environment in which they will likely function.

Critical developmental periods of vulnerability in dystonia

“…Evidence from Drosophila melanogaster larvae shows that perturbations to spontaneously generated activity during the embryonic stage causes lasting behavioural defects in the form of delayed and abnormal crawling behaviour [55,56]. Experiments in both Drosophila and mice show that similar perturbations can also enhance seizure susceptibility, presumably reflecting long-lasting alterations to neuronal circuit function, and that normalising activity during the same stage can rescue these phenotypes [50,57,58].…”