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.

Critical periods are developmental windows during which neural circuits effectively adapt to the new sensory environment. Animal models of fragile X syndrome (FXS), a common monogenic autism spectrum disorder (ASD), exhibit profound impairments of sensory experience-driven critical periods. However, it is not known whether the causative fragile X mental retardation protein (FMRP) acts uniformly across neurons, or instead manifests neuron-specific functions. Here, we use the genetically-tractable Drosophila brain antennal lobe (AL) olfactory circuit of both sexes to investigate neuron-specific FMRP roles in the odorant experience-dependent remodeling of the olfactory sensory neuron (OSN) innervation during an early-life critical period. We find targeted OSN class-specific FMRP RNAi impairs innervation remodeling within AL synaptic glomeruli, whereas global dfmr1 null mutants display relatively normal odorant-driven refinement. We find both OSN cell autonomous and cell non-autonomous FMRP functions mediate odorant experience-dependent remodeling, with AL circuit FMRP imbalance causing defects in overall glomerulus innervation refinement. We find OSN class-specific FMRP levels bidirectionally regulate critical period remodeling, with odorant experience selectively controlling OSN synaptic terminals in AL glomeruli. We find OSN class-specific FMRP loss impairs critical period remodeling by disrupting responses to lateral modulation from other odorant-responsive OSNs mediating overall AL gain control. We find that silencing glutamatergic AL interneurons reduces OSN remodeling, while conversely, interfering with the OSN class-specific GABA A signaling enhances remodeling. These findings reveal control of OSN synaptic remodeling by FMRP with neuron-specific circuit functions, and indicate how neural circuitry can compensate for global FMRP loss to reinstate normal critical period brain circuit remodeling.