The goal of this project is to understand mechanisms of trans-synaptic communication during development and plasticity of synapses. During the past many years, with support from this grant, we have pioneered work with fundamental implications to our understanding of synaptic plasticity signals, demonstrating an essential role for Wnts in these processes. The linkage between Wnts and severe neurological conditions, such as Alzheimer?s disease, and schizophrenia1,2, makes our findings particularly impactful. During the past 5 years, the funding stability provided by this MERIT award, enabled us to significantly expand our field of expertise, which resulted in several highly significant and unexpected discoveries, which form the basis of the work proposed over the next 5 years of the award. In particular, we documented a totally novel mode of intercellular communication, ViSyToR (Viral Synaptic Transfer of RNA) a retroviral-like mechanism of trans-cellular mRNA transfer. In addition, we provided compelling evidence that ViSyToR was used to carry mRNA encoding a master regulator of synaptic plasticity, Arc/Arg2.1. In the proposed extension of this MERIT award we will (a) test the hypothesis that Copia retrotransposon forms have a physiological role in trans-synaptic communication, (b) determine if other Gag-encoding genes and transposons function in trans-synaptic communication using the ViSyToR pathway, and (c) unravel mechanisms of ViSyToR function at synapses, including interactions between Wg and dArc1.

Public Health Relevance

Understanding mechanisms of communication between cells in the nervous system is crucial to elucidating the processes that go awry in neurological disorders, such as Alzheimer?s disease and schizophrenia. This projects centers on the discovery and characterization of a novel mechanism of cellular communication in the nervous system, called ViSyToR (Viral Synaptic Transfer of RNA) using viral-like processes to transmit a signal across cells. The results from these studies are expected to significantly expand our knowledge of signal transmission in the nervous system and provide platforms for the development of therapies to treat neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH070000-18
Application #
10057271
Study Section
Special Emphasis Panel (NSS)
Program Officer
Panchision, David M
Project Start
2003-12-01
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
18
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Neurosciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ashley, James; Cordy, Benjamin; Lucia, Diandra et al. (2018) Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons. Cell 172:262-274.e11
Budnik, Vivian; Ruiz-CaƱada, Catalina; Wendler, Franz (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17:160-72
Packard, Mary; Jokhi, Vahbiz; Ding, Baojin et al. (2015) Nucleus to Synapse Nesprin1 Railroad Tracks Direct Synapse Maturation through RNA Localization. Neuron 86:1015-1028