Broadie Laboratory

Experience-Dependent MAPK/ERK Signaling in Glia Regulates Critical Period Remodeling of Synaptic Glomeruli

AUTHORS

ABSTRACT

Early-life critical periods allow initial sensory experience to remodel brain circuitry so that synaptic connectivity can be optimized to environmental input. In the Drosophila juvenile brain, olfactory sensory neuron (OSN) synaptic glomeruli are pruned by glial phagocytosis in dose-dependent response to early odor experience during a well-defined critical period. Extracellular signal-regulated kinase (ERK) separation of phases-based activity reporter of kinase (SPARK) biosensors reveal experience-dependent signaling in glia during this critical period. Glial ERK-SPARK signaling is depressed by removal of Draper receptors orchestrating glial phagocytosis. Cell-targeted genetic knockdown of glial ERK signaling reduces olfactory experience-dependent glial pruning of the OSN synaptic glomeruli in a dose-dependent mechanism. Noonan Syndrome is caused by gain-of-function mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) inhibiting ERK signaling, and a glial-targeted patient-derived mutation increases experience-dependent glial ERK signaling and impairs experience-dependent glial pruning of the OSN synaptic glomeruli. We conclude that critical period experience drives glial ERK signaling that is required for dose-dependent pruning of brain synaptic glomeruli, and that altered glial ERK signaling impairs this critical period mechanism in a Noonan Syndrome disease model.