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Principal Investigator: Yuan Wang
Organization: FLORIDA STATE UNIVERSITY
Fiscal Year: 2024
Award: $398,888
Funding agency: National Institute of Mental Health
Project Summary
This project will address the question of how abnormal synaptic development emerges in neurodevelopmental
disorders. Our overall hypothesis is that disorganized synaptic adhesion and delayed functional assembly of
synaptic vesicles (SVs) impair the formation and physiological maturation of presynaptic terminals, which triggers
subsequent developmental deficits in synaptic connectivity and function. We will test this hypothesis in Fragile X
syndrome (FXS), a leading inheritable form of autism and intellectual disability caused by functional loss of
Fragile X mental retardation protein (FMRP). Experimental observations will utilize the evolutionally conserved
endbulb terminals that are readily accessible for in vivo cell-autonomous characterizations in chicken embryos.
We will pursue two specific aims to test several important hypotheses derived from our preliminary studies.
· In Specific Aim 1, we will determine the role of FMRP-regulated synaptic adhesion in presynaptic
terminal formation. We hypothesize that axonal FMRP promotes terminal formation, stabilization, and
selective retraction through developmentally profiled synaptic adhesion. To test this hypothesis, we will
use cell-group specific and temporally-controlled genetic manipulations combined with in vivo live
imaging to identify the exact actions of FMRP-mediated axon transport vs. protein translation in dynamic
terminal turnover. We will also identify FMRP-regulated synaptic adhesion elements in developing
terminals and assess the effects of correcting these elements on FMRP loss-induced presynaptic and
axon alterations.
· In Specific Aim 2, we will determine the role of FMRP-regulated synaptotagmin (Syt) in functional
maturation of presynaptic terminals. Syt1/2 are primary calcium sensors on SVs that trigger vesicle fusion
and neurotransmitter release. We hypothesize that FMRP regulates presynaptic functional maturation by
controlling the timely upregulation of Syt2 in nascent terminals. To test this hypothesis, we will determine
the effects of expressing Syt2 on FMRP loss-induced deficits in SV activity, presynaptic protein
machinery, and glutamate release. We will also determine the interplay between synaptic adhesion
regulation and SV assembly under FMRP control using rescue studies.
Together, these results will identify an origin of defective synaptic phenotypes, a hallmark of neurodevelopmental
disorders. This knowledge is of vital importance because it will help establish a sensitive time window and identify
novel therapeutic candidates for preventing, or at least reducing, the progress of synaptic deficits in FXS and
other neurodevelopmental disorders.
Terms: <ASD><Acute><Adhesion Molecule><Adhesions><Autism><Autistic Disorder><Axon><Axon Terminals><Axonal Transport><Axoplasmic Transport><Behavioral><Brain><Brain Nervous System><Calcium><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cells><Chick Embryo><Chickens><Cues><Development><Drugs><Dysfunction><Early Infantile Autism><Elements><Embryo><Embryonic><Encephalon><Escalante syndrome><Evolution><Exocytosis><FMR-1 Protein><FMR1 Protein><FMR1 gene><FMRP><FMRP protein><FRAXA><Fragile X><Fragile X Mental Retardation 1 Gene><Fragile X Mental Retardation Protein><Fragile X Syndrome><Functional Imaging><Functional disorder><Gallus domesticus><Gallus gallus><Gallus gallus domesticus><Generations><Glutamates><Goals><Hereditary><Human><Image><Impairment><Infantile Autism><Inherited><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Kanner's Syndrome><Knowledge><L-Glutamate><Location><Mammalia><Mammals><Martin-Bell Syndrome><Martin-Bell-Renpenning syndrome><Mediating><Medication><Modern Man><Molecular><Nerve Impulse Transmission><Nerve Transmission><Neural Transmission><Neurodevelopmental Disorder><Neurological Development Disorder><Neuronal Transmission><Outcome><Pathway interactions><Pharmaceutical Preparations><Phenotype><Physiologic><Physiologic Imaging><Physiological><Physiopathology><Presynaptic Nerve Endings><Presynaptic Terminals><Probability><Process><Protein Deficiency><Proteins><Publishing><RNA-Binding Proteins><Regulation><Renpenning syndrome 2><Resolution><Role><Synapses><Synaptic><Synaptic Boutons><Synaptic Terminals><Synaptic Transmission><Synaptic Vesicles><Synaptic plasticity><System><Testing><Time><Translations><Up-Regulation><Upregulation><Vesicle><X-linked mental deficiency-megalotestes syndrome><X-linked mental retardation with fragile X syndrome><X-linked mental retardation-fragile site 1 syndrome><adhesion receptor><autism spectral disorder><autism spectrum disorder><autism-fragile X (AFRAX) syndrome><autistic spectrum disorder><axon signaling><axon-glial signaling><axonal signaling><cell adhesion protein><chicken embryo><deficiency of protein><develop therapy><developmental><drug/agent><fra(X) syndrome><fra(X)(28) syndrome><fra(X)(q27) syndrome><fra(X)(q27-28) syndrome><fragile X FMR1 protein><fragile X mental retardation 1><fragile X mental retardation-1 protein><fragile X-mental retardation syndrome><fragile Xq syndrome><fragile site mental retardation 1><functional loss><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><glia signaling><glial signaling><glutamatergic><imaging><in vivo><intellectual and developmental disability><intervention development><knock-out animal><knockout animal><limited intellectual functioning><macro-orchidism-marker X (MOMX) syndrome><macro-orchidism-marker X syndrome><mar(X) syndrome><marker X syndrome><mental retardation-macroorchidism syndrome><nerve signaling><neural circuit><neural circuitry><neural signaling><neurocircuitry><neurodevelopmental disease><neuronal signaling><neuropathologic><neuropathological><neuropathology><neurotransmission><neurotransmitter release><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><pathway><physiological imaging><postsynaptic><pre-synaptic nerve><pre-synaptic neurons><presynaptic><presynaptic nerve><presynaptic neurons><prevent><preventing><protein expression><protein function><resolutions><sensor><social role><structural imaging><synapse><synapse formation><synaptic circuit><synaptic circuitry><synaptogenesis><synaptotagmin><therapeutic candidate><therapy development><translation><treatment development>