Neuron-Specific FMRP Roles in Experience-Dependent Remodeling of Olfactory Brain Innervation during an Early-Life Critical Period

Abstract

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.

Dysregulation of BMP, Wnt, and Insulin Signaling in Fragile X Syndrome

“…At the Drosophila glutamatergic NMJ, Wnt/BMP/ILP ligands and their receptors participate in bidirectional trans -synaptic neuron-muscle and intercellular neuron-glia communication ( Dani et al, 2012 ; Mahoney et al, 2016 ; Chou et al, 2020 ). More generally, interfering with these secreted intercellular signaling pathways in the CNS causes aberrant neurogenesis/gliogenesis, synaptogenesis, and neural circuit remodeling starting in embryonic stages ( Luo et al, 2010 ; Guo et al, 2011 ), and consequently generating defects in sensory processing, coordinated movement, and higher brain function ( Goel et al, 2019 ; Golovin et al, 2021 ). Consistently, autistic and neurodegenerative disorders are characterized by poorly regulated secretion of BMPs, Wnts, and ILPs ( Timberlake et al, 2017 ; de Mello et al, 2019 ; Serafino et al, 2020 ; Russo and Wharton, 2022 ).…”

Presynaptic contact and activity opposingly regulate postsynaptic dendrite outgrowth

“…Critical periods are developmental windows of heightened neural plasticity that are present from vertebrates ( Kalb, 1994 ; Keck et al, 2017 ; Takesian and Hensch, 2013 ; Walton et al, 1992 ) to insects ( Caglayan and Gilbert, 1987 ; Elekonich et al, 2003 ; Hartfelder et al, 1995 ; Levine et al, 1986 ; Morgan et al, 1998 ). In Drosophila , critical periods have been identified in the late embryo/early larva ( Ackerman et al, 2021 ; Crisp et al, 2011 ; Fushiki et al, 2013 ; Giachello et al, 2021 ; Giachello and Baines, 2015 ; Hartwig et al, 2008 ; Jarecki and Keshishian, 1995 ; Tripodi et al, 2008 ) and in the newly eclosed adult ( Doll et al, 2017 ; Doll and Broadie, 2016 ; Doll and Broadie, 2015 ; Golovin et al, 2021 ; Golovin et al, 2019 ). Altered activity during the critical period can lead to long-lasting defects in neuronal morphology and behavior ( Ackerman et al, 2021 ; Crisp et al, 2011 ; Fushiki et al, 2013 ; Giachello et al, 2021 ; Giachello and Baines, 2015 ; Hartwig et al, 2008 ; Jarecki and Keshishian, 1995 ; Tripodi et al, 2008 ).…”

Deficits in olfactory system neurogenesis in neurodevelopmental disorders

“…Returning to the Drosophila model of FXS, there is evidence that dFMRP plays a significant role in activity‐ and experience‐dependent remodeling of the olfactory system (Doll et al, 2017; Golovin et al, 2021). Alterations to critical period activity in the antennal lobe medial projection neuron 2 (AL‐mPN2) population in dfmr1‐ flies failed to produce changes in axonal branching and bouton area that were observed in control flies (Doll et al, 2017).…”

“…These results suggest a vital role for dFMRP in mediating activity‐dependent synaptic refinement during the critical period. In WT flies, odorant exposure during an early life critical period strongly reduces antennal lobe glomerular innervation by OSNs that detect that odorant (Golovin et al, 2021). Surprisingly, RNAi‐mediated dFMRP knockdown in a single class of OSNs impaired odorant‐dependent remodeling during this critical period.…”