Short and long-term activity-dependent changes in synaptic efficacy are essential to brain function. Experimental evidence indicates that activity-induced long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are cellular correlates to learning and memory and experience-dependent refinement of neural connections. The molecular mechanisms underlying synaptic plasticity are diverse and can be characterized as presynaptic or postsynaptic, depending on whether neurotransmitter release, or a target neuron's sensitivity to the released transmitter, is modified. Presynaptic LTP and LTD have now been observed across many brain regions, including the hippocampus, both at excitatory and inhibitory synapses, and growing evidence indicates that presynaptic LTP/LTD may underlie important forms of learning. However, the synaptic learning rules for these forms of plasticity are poorly characterized, and our understanding of presynaptic mechanisms lags far behind the postsynaptic side. Presynaptic plasticity can originate entirely in the presynaptic terminal or it may require retrograde signaling from postsynaptic to presynaptic compartments. In the last decade, retrograde signaling emerged as a widely expressed mechanism by which postsynaptic neurons can control their own inputs and, by this means, regulate neural circuits over short and long-time scales. The best characterized retrograde signaling system is the endocannabinoid (eCB) system, and while much has been learned from this system, important knowledge gaps remain for other retrograde messengers including the type of activity required for mobilization, the mechanisms of postsynaptic release and presynaptic action, and ultimately, the precise physiological role of retrograde signaling at a synapse in a given neural circuit. In this research proposal, we will address these outstanding questions by focusing on three distinct hippocampal synapses using state-of-the-art electrophysiology, molecular pharmacology, optogenetics, and live imaging in acute brain slices. Specifically, we will test the hypothesis that presynaptic protein synthesis is necessary for eCB-mediated LTD at inhibitory synapses. In addition, we will determine the mechanism and functional consequence of a novel form of presynaptic LTP at a key, but remarkably understudied, excitatory synapse in dentate gyrus. Finally, we will test the hypothesis that retrograde signaling negatively regulates a powerful detonator synapse. Knowledge derived from these investigations will provide new mechanistic insights on retrograde signaling at central synapses and may also uncover novel roles for presynaptic plasticity in the hippocampal network. A better understanding of presynaptic plasticity represents a significant step forward in the development of strategies to restore synaptic function in diseased brain states, such as autism, neurodegenerative diseases (e.g. Alzheimer's disease, Huntington's disease), schizophrenia, epilepsy and addictive behaviors.

Public Health Relevance

Brain functions heavily rely on the dynamic properties of synaptic connections between neurons, and growing evidence indicates that synaptic dysfunction underlies a number of devastating brain disease states. Understanding the mechanisms and functional consequences of activity-dependent changes in synaptic transmission under normal conditions represents a significant step forward in the development of strategies to control synaptic dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA017392-14
Application #
9230355
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sorensen, Roger
Project Start
2003-08-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
14
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Araque, Alfonso; Castillo, Pablo E; Manzoni, Olivier J et al. (2017) Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124:13-24
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Oh, Won Chan; Lutzu, Stefano; Castillo, Pablo E et al. (2016) De novo synaptogenesis induced by GABA in the developing mouse cortex. Science 353:1037-1040
Batista, Gervasio; Monday, Hannah R (2016) Visualizing Local Protein Synthesis and Its Modulation by FMRP and Visual Experience. J Neurosci 36:11834-11836
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Younts, Thomas J; Monday, Hannah R; Dudok, Barna et al. (2016) Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release. Neuron 92:479-492
Park, Joongkyu; Chávez, Andrés E; Mineur, Yann S et al. (2016) CaMKII Phosphorylation of TARP?-8 Is a Mediator of LTP and Learning and Memory. Neuron 92:75-83
Ben-Simon, Yoav; Rodenas-Ruano, Alma; Alviña, Karina et al. (2015) A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity. Cell Rep 12:396-404

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