Circadian control in the timing of critical periods duringDrosophilalarval neuronal development.

Critical periods (CPs) of development are temporal windows of heightened neural plasticity. Activity perturbation during CPs can produce significant, and permanent, alterations to the development of neural circuits. In this study we report a circadian mechanism underlying the timing of CPs inDrosophilaembryonic and larval development. These CPs occur at ~24 hr intervals and are open to manipulation through blue light (BL)-activation of the circadian regulator Cryptochrome (CRY). This manipulation is sufficient to destabilize the larval CNS, evidenced by an induced seizure phenotype when tested at third instar (L3). In addition to CRY nulls, genetic ablation of the period gene also mitigates the BL exposure seizure phenotype and, moreover, alleles of period that affect circadian timing alter the timing of the CPs. Our analysis shows a clear role for the main clock neuropeptide, pigment dispersing factor (PDF), to transduce the output of these CPs. Targeted PDF receptor knockdown, in either GABAergic or CRY-positive neurons, is sufficient to prevent the CRY-mediated seizure phenotype. This study is a first demonstration of a circadian mechanism inDrosophilalarvae, and whilst this alone is of major significance, our results highlight the potential of usingDrosophilalarvae as a model to investigate the impact of circadian rhythms on early neuronal development in higher organisms, which remains experimentally challenging.