Activity-regulated modulation of synapse function lies at the heart of molecular theories of learning and neural development, and is disrupted by diseases and disorders including schizophrenia, autism spectrum disorders, and obsessive compulsive disorder. In glutamatergic synapses, multi-domain proteins establish the core of the postsynaptic density (PSD), the structure which links neurotransmitter receptors to the actin cytoskeleton and to intracellular signaling pathways. Though the structures of PSDs and synapses are known to change dramatically in diverse paradigms of synaptic plasticity, it is not known to what extent structure alone-rather than molecular content such as receptor number-can control synaptic strength. We have developed tools to address this. Thus, in cultured neurons from rat hippocampus, we will use single-molecule imaging approaches along with electrophysiology and new molecular tools to tackle this central question of synapse biology. First, we will follow up on intriguing work from our prior funding period indicating that scaffold molecules in the PSD are distributed with substantial peaks and valleys of density across the PSD parallel to the membrane. We hypothesize that these peaks establish a similar organization of other proteins at points that stretch from the presynaptic terminal too deep into the spine, and particularly that PSD structure guides protein organization within the active zone, thus assuring the optimal alignment of vesicle fusion apparatus with clustered postsynaptic receptors. Second, we ask whether PSD substructure-rather than its overall size-regulates receptor activation and thus synaptic strength. We test this using new techniques to monitor postsynaptic NMDAR or AMPAR activation during concurrent super-resolution imaging to measure postsynaptic structure. Third, using a newly developed method, we analyze for the first time the distribution of vesicle release sites within single active zones. For these aims, we test the role of the key scaffolding molecule Shank in maintaining transsynaptic structural organization, both to test fundamental mechanisms and because its failure to do so may contribute significantly to human disease. The answers to these questions provide a new and detailed view of how synaptic function arises from its notoriously detailed architecture. Perhaps most importantly, they will provide an important platform on which to test hypotheses regarding the molecular basis of disorders that disrupt synaptic transmission.

Public Health Relevance

New experiences are encoded in brain circuits by altering the performance of the synaptic connections between neurons. This project aims to assess previously unexplored features of synapses that may allow their performance to be adjusted in heretofore unexpected ways, and will thus help understand the biological basis of memory formation. Further, because mental illness frequently arises from aberrant synapse function, these experiments will help determine the origin and potential treatments for diseases including schizophrenia and autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080046-11
Application #
9380975
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Driscoll, Jamie
Project Start
2007-04-05
Project End
2019-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cijsouw, Tony; Ramsey, Austin M; Lam, TuKiet T et al. (2018) Mapping the Proteome of the Synaptic Cleft through Proximity Labeling Reveals New Cleft Proteins. Proteomes 6:
Chen, Haiwen; Tang, Ai-Hui; Blanpied, Thomas A (2018) Subsynaptic spatial organization as a regulator of synaptic strength and plasticity. Curr Opin Neurobiol 51:147-153
Divakaruni, Sai Sachin; Van Dyke, Adam M; Chandra, Ramesh et al. (2018) Long-Term Potentiation Requires a Rapid Burst of Dendritic Mitochondrial Fission during Induction. Neuron 100:860-875.e7
Biederer, Thomas; Kaeser, Pascal S; Blanpied, Thomas A (2017) Transcellular Nanoalignment of Synaptic Function. Neuron 96:680-696
Li, Tuo P; Song, Yu; MacGillavry, Harold D et al. (2016) Protein Crowding within the Postsynaptic Density Can Impede the Escape of Membrane Proteins. J Neurosci 36:4276-95
Tang, Ai-Hui; Chen, Haiwen; Li, Tuo P et al. (2016) A trans-synaptic nanocolumn aligns neurotransmitter release to receptors. Nature 536:210-4
MacGillavry, Harold D; Kerr, Justin M; Kassner, Josh et al. (2016) Shank-cortactin interactions control actin dynamics to maintain flexibility of neuronal spines and synapses. Eur J Neurosci 43:179-93
Li, Tuo P; Blanpied, Thomas A (2016) Control of Transmembrane Protein Diffusion within the Postsynaptic Density Assessed by Simultaneous Single-Molecule Tracking and Localization Microscopy. Front Synaptic Neurosci 8:19
Perez de Arce, Karen; Schrod, Nikolas; Metzbower, Sarah W R et al. (2015) Topographic Mapping of the Synaptic Cleft into Adhesive Nanodomains. Neuron 88:1165-1172
Kim, Karam; Lakhanpal, Gurpreet; Lu, Hsiangmin E et al. (2015) A Temporary Gating of Actin Remodeling during Synaptic Plasticity Consists of the Interplay between the Kinase and Structural Functions of CaMKII. Neuron 87:813-26

Showing the most recent 10 out of 26 publications