Fragile X mental retardation protein coordinates neuron-to-glia communication for clearance of developmentally transient brain neurons

Abstract

In the developmental remodeling of brain circuits, neurons are removed by glial phagocytosis to optimize adult behavior. Fragile X mental retardation protein (FMRP) regulates neuron-to-glia signaling to drive glial phagocytosis for targeted neuron pruning. We find that FMRP acts in a mothers against decapentaplegic (Mad)-insulin receptor (InR)-protein kinase B (Akt) pathway to regulate pretaporter (Prtp) and amyloid precursor protein-like (APPL) signals directing this glial clearance. Neuronal RNAi of Drosophila fragile X mental retardation 1 ( dfmr1 ) elevates mad transcript levels and increases pMad signaling. Neuronal dfmr1 and mad RNAi both elevate phospho–protein kinase B (pAkt) and delay neuron removal but cause opposite effects on InR expression. Genetically correcting pAkt levels in the mad RNAi background restores normal remodeling. Consistently, neuronal dfmr1 and mad RNAi both decrease Prtp levels, whereas neuronal InR and akt RNAi increase Prtp levels, indicating FMRP works with pMad and insulin signaling to tightly regulate Prtp signaling and thus control glial phagocytosis for correct circuit remodeling. Neuronal dfmr1 and mad and akt RNAi all decrease APPL levels, with the pathway signaling higher glial endolysosome activity for phagocytosis. These findings reveal a FMRP-dependent control pathway for neuron-to-glia communication in neuronal pruning, identifying potential molecular mechanisms for devising fragile X syndrome treatments.

Experience-dependent glial pruning of synaptic glomeruli during the critical period

“…Glia subclasses differentially refine OSN synaptic architecture in a Draper-dependent mechanism 15 . Three glial classes function as phagocytes and can act cooperatively for neuronal phagocytosis in Drosophila juvenile brains 47 , 75 . In the critical period, we find only ensheathing glia employ Draper for experience-dependent synapse pruning (Fig.…”

Expression of Transposable Elements in the Brain of the Drosophila melanogaster Model for Fragile X Syndrome

“…It has been widely used to investigate FMR1 functions at the molecular, genetic, and cellular levels, as Drosophila Fmr1 mutants exhibit several FXS phenotypes [6]. In the Drosophila model, FMRP is required for experience-dependent changes in synaptic connectivity during the development of the neuronal circuits for sensory input as well as in regulating neuron-to-glia communication in neuronal circuits [28]. A role of Drosophila FMRP was demonstrated in the regulation of TEs in the gonads [13].…”