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Principal Investigator: Lu Chen
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $77,357
Funding agency: National Institute of Neurological Disorders and Stroke
Principal Investigator: Chen, Lu
Summary
Our research focuses on uncovering the molecular mechanisms of a form of non-Hebbian synaptic
plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity,
homeostatic plasticity operates under different rules as a “corrective” mechanism to prevent run-away Hebbian
plasticity. Compared to Hebbian plasticity, the molecular and cellular mechanisms underlying homeostatic
synaptic plasticity is much less understood, and their implication in neuropsychiatric disorders is largely
unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling
pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression,
resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate
that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice
induces run away Hebbian plasticity as manifested by greatly enhanced LTP and diminished LTD. As a
behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced
behavioral flexibility when raised in enriched environment. Together, our work establishes a link between
synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic
plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project is to gain further
understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity. Specifically,
we will focus on three aspects of RA signaling in the context of homeostatic synaptic plasticity: the trans-synaptic
cell adhesion molecule neurexins, the BDNF-TrkB retrograde signaling, and the functional interaction between
FMRP and RA receptor RARα. Together, results from this proposed study will identify new candidate molecular
tools for investigating in vivo function of homeostatic synaptic plasticity, and also provide insight into discovering
new drug targets for treating FXS and potentially other mental disorders.
Relevance
This project will investigate molecular mechanisms through which synaptic RA signaling regulates synaptic
strength in a homeostatic manner. Recent studies using FXS model mice and human FXS patient neurons
establish that defective RA-dependent homeostatic synaptic plasticity is a major synaptic dysfunction phenotype
associated with fragile-x syndrome. Thus, uncovering additional molecular players critically involved in
homeostatic plasticity will provide the opportunity to discover new drug targets for treating FXS and other forms
of mental illness in which circuit maladaptation due to compromised homeostatic plasticity is a major contributor
to disease symptoms.
PHS 398/2590 (Rev. 11/07) Page 1 Summary
Terms: <21+ years old><AMPA Receptors><ATRA><Address><Adhesion Molecule><Adult><Adult Human><Affect><Ammon Horn><Animals><BDNF><Behavioral><Binding><Brain-Derived Neurotrophic Factor><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Communication and Signaling><Cell Signaling><Cognitive deficits><Cornu Ammonis><Coupled><Data><Development><Disease><Disorder><Drug Targeting><Dysfunction><Escalante syndrome><Event><Excitatory Synapse><Exhibits><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 disorder><Funding Opportunities><Gene Transcription><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Hereditary><Hippocampus><Human><Impairment><Inherited><Inhibitory Synapse><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intracellular Communication and Signaling><Investigation><Laboratories><Learning><Link><Martin-Bell Syndrome><Martin-Bell-Renpenning syndrome><Mediating><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Nature><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neurosciences><Patients><Phenotype><Physiologic><Physiological><Physiopathology><Principal Investigator><Process><Proteins><Psychiatric Disease><Psychiatric Disorder><R-Series Research Projects><R01 Mechanism><R01 Program><RAR alpha><RAR-α><RARalpha><RARα><RNA Expression><RNA Splicing><Regulation><Renpenning syndrome 2><Research><Research Grants><Research Project Grants><Research Projects><Retinoic Acid><Retinoic Acid Receptor><Role><Runaway><Sensory><Series><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Splicing><Structure><Symptoms><Synapses><Synaptic><Synaptic plasticity><Testing><Trans Vitamin A Acid><Transcription><Translations><Tretinoin><Tretinoinum><Variant><Variation><Vitamin A Acid><Work><X-linked mental deficiency-megalotestes syndrome><X-linked mental retardation with fragile X syndrome><X-linked mental retardation-fragile site 1 syndrome><adulthood><all-trans-Retinoic Acid><all-trans-Vitamin A acid><autism-fragile X (AFRAX) syndrome><biological signal transduction><cell adhesion protein><cognitive defects><cognitive function><developmental><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><flexibility><flexible><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><genome mutation><hippocampal><in vivo><insight><intellectual and developmental disability><limited intellectual functioning><macro-orchidism-marker X (MOMX) syndrome><macro-orchidism-marker X syndrome><mar(X) syndrome><marker X syndrome><mental illness><mental retardation-macroorchidism syndrome><mouse model><murine model><neural circuit><neural circuitry><neurocircuitry><neurological disease><neuronal><neuropsychiatric disease><neuropsychiatric disorder><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathophysiology><postsynaptic><presynaptic><prevent><preventing><psychiatric illness><psychological disorder><response><retinoic acid receptor alpha><retinoic acid receptor α><social role><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><tool><trafficking><trans-Retinoic Acid><translation>