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Principal Investigator: Francis Sang Yong Lee
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $526,214
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Synaptic transmission and its plasticity are based on a core group of synaptic receptors that rapidly sense
neurotransmitters such as glutamate and GABA. Neurotrophins, such as brain-derived neurotrophic factor
(BDNF), are typically thought to signal on slower time scales, but have also been shown to regulate the induction
and expression of synaptic plasticity. Despite both neurotransmitter and neurotrophin signaling underlying most
forms of synaptic plasticity and serving as major mediators of the pathophysiology and treatment of
neurogenerative and neuropsychiatric disorders, little is known about how these different receptor classes work
in concert through direct and indirect forms of crosstalk. Motivated by the paucity of direct tests of
neurotrophin/neurotransmitter crosstalk, our preliminary studies have indicated that the neurotrophin receptor,
TrkB, and metabotropic glutamate receptor 5 (mGluR5) are able to mutually regulate each other in both native
and heterologous systems. In contrast to previous studies which have focused on the ability of GPCRs to activate
RTK signaling, we have identified one of the first examples of an RTK (TrkB) engaging a GPCR (mGluR5) as a
signaling effector. In this proposal, we will test the hypothesis that mGluR5 is a critical mediator of TrkB effects
by amplifying and altering the spatiotemporal dynamics of downstream signaling to canonical effectors to drive
a unique form of crosstalk-dependent synaptic plasticity. Collectively, this new form of TrkB-mGluR5 signaling
may contribute to the diverse higher order nervous system functions related to neural plasticity that have been
attributed to the BDNF-TrkB neurotrophin system. Aim 1 will define BDNF-TrkB receptor mediated signaling
crosstalk with mGluR5. Aim 2 will decipher the signaling mechanisms that regulate TrkB/mGluR5 crosstalk. Aim
3 will determine the impact of TrkB-mGluR5 synergy on BDNF-LTP and mGluR5-LTD.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Acute><Aminalon><Aminalone><Ammon Horn><Assay><Attention><Attenuated><BDNF><BDNF Receptor><BDNF/NT-3 Growth Factors Receptor><Binding><Binding Proteins><Bioassay><Biological Assay><Biosensor><Brain><Brain Nervous System><Brain-Derived Neurotrophic Factor><Brain-Derived Neurotrophic Factor Receptor><CNS Nervous System><CNS plasticity><Calcium><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Complex><Cornu Ammonis><Data><Degenerative Neurologic Disorders><Dendrites><Development><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalon><Event><Family><Family member><Fluoxetin><Fluoxetine><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><G-Proteins><GABA><GDP Dissociation Factor><GDP Dissociation Stimulators><GDP Exchange Factors><GDP-GTP Exchange Protein><GDP-GTP Reversing Factors><GP145-TRKB><GPCR><GPCR Signaling><GRIK1 gene product><GTP GDP exchange factor><GTP-Binding Proteins><GTP-Regulatory Proteins><Genetic><Glutamates><Growth Agents><Growth Factor><Growth Substances><Guanine><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Exchange Factors><Guanine Nucleotide Exchange Protein><Guanine Nucleotide Regulatory Proteins><Guanine Nucleotide Releasing Factors><Guanyl-Nucleotide Exchange Factor><Guanyl-Nucleotide Releasing Factor><Hippocampus><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><KO mice><Ketamine><Kinases><Knock-out Mice><Knockout Mice><L-Glutamate><Ligand Binding Protein><Ligand Binding Protein Gene><Long-Term Depression><Long-Term Potentiation><Long-Term Synaptic Depression><Longterm Potentiation><Mediating><Mediator><Membrane Channels><Metabotropic Glutamate Receptors><Molecular><Molecular Interaction><NGF Receptors><NTRK2 Receptor><Nerve Cells><Nerve Growth Factor Receptors><Nerve Transmitter Substances><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Physiology><Neural Cell><Neural Degenerative Diseases><Neural Transmission><Neural degenerative Disorders><Neuraxis><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic function><Neurological function><Neuromodulator><Neuronal Plasticity><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Neurotransmitters><Neurotrophic Factor Receptor><Neurotrophic Tyrosine Kinase Receptor Type 2><Neurotrophin Receptors><Null Mouse><Output><PTK Receptors><Pathway interactions><Pharmacology><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiopathology><Property><Protein Binding><Protein Secretion><Proteins Growth Factors><Prozac><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Role><Series><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Synapses><Synaptic><Synaptic Receptors><Synaptic Transmission><Synaptic plasticity><System><TRKB Tyrosine Kinase><Testing><Time><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Work><anti-depressant agent><anti-depressant drugs><anti-depressant effect><anti-depressants><anti-depressive agents><antidepressant effect><attenuate><attenuates><biological sensor><biological signal transduction><bound protein><central nervous system plasticity><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><desensitization><developmental><electrophysiological><exchange factor><extracellular><fluorescence imaging><fluorescent imaging><gamma-Aminobutyric Acid><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glutamatergic><hippocampal><longterm depression><longterm synaptic depression><metabotropic glutamate receptor 5><nervous system function><neural plasticity><neurodegenerative illness><neuronal><neuronal circuit><neuronal circuitry><neuroplastic><neuroplasticity><neuropsychiatric disease><neuropsychiatric disorder><neurotrophic factor><neurotrophin><neutrophin><novel><optogenetics><pathophysiology><pathway><postsynaptic><receptor><receptor-mediated signaling><response><social role><spatiotemporal><synapse><synergism><tool><trafficking><treatment strategy><trkB Receptor><trkB(gp145) Protein><γ-Aminobutyric Acid>