Activity-Dependent Remodeling of Drosophila Olfactory Sensory Neuron Brain Innervation during an Early-Life Critical Period.

Critical periods are windows of development when the environment has a pronounced effect on brain circuitry. Models of neurodevelopmental disorders, including autism spectrum disorders, intellectual disabilities, and schizophrenia, are linked to disruption of critical period remodeling. Critical periods open with the onset of sensory experience; however, it remains unclear exactly how sensory input modifies brain circuits. Here, we examine olfactory sensory neuron (OSN) innervation of the Drosophila antennal lobe of both sexes as a genetic model of this question. We find that olfactory sensory experience during an early-use critical period drives loss of OSN innervation of antennal lobe glomeruli and subsequent axon retraction in a dose-dependent mechanism. This remodeling does not result from olfactory receptor loss or OSN degeneration, but rather from rapid synapse elimination and axon pruning in the target olfactory glomerulus. Removal of the odorant stimulus only during the critical period leads to OSN reinnervation, demonstrating that remodeling is transiently reversible. We find that this synaptic refinement requires the OSN-specific olfactory receptor and downstream activity. Conversely, blocking OSN synaptic output elevates glomeruli remodeling. We find that GABAergic neurotransmission has no detectable role, but that glutamatergic signaling via NMDA receptors is required for OSN synaptic refinement. Together, these results demonstrate that OSN inputs into the brain manifest robust, experience-dependent remodeling during an early-life critical period, which requires olfactory reception, OSN activity, and NMDA receptor signaling. This work reveals a pathway linking initial olfactory sensory experience to glutamatergic neurotransmission in the activity-dependent remodeling of brain neural circuitry in an early-use critical period.SIGNIFICANCE STATEMENT Neurodevelopmental disorders manifest symptoms at specific developmental milestones that suggest an intersection between early sensory experience and brain neural circuit remodeling. One classic example is Fragile X syndrome caused by loss of an RNA-binding translation regulator of activity-dependent synaptic refinement. As a model, Drosophila olfactory circuitry is well characterized, genetically tractable, and rapidly developing, and thus ideally suited to probe underlying mechanisms. Here, we find olfactory sensory neurons are dramatically remodeled by heightened sensory experience during an early-life critical period. We demonstrate removing the olfactory stimulus during the critical period can reverse the connectivity changes. We find that this remodeling requires neural activity and NMDA receptor-mediated glutamatergic transmission. This improved understanding may help us design treatments for neurodevelopmental disorders.