DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning

Boaz Mohar; Gabriela Michel; Yi Zhi Wang; Veronica Hernandez; Jonathan B. Grimm; Jin Yong Park; Ronak Patel; Morgan Clarke; Timothy A. Brown; Cornelius Bergmann; Kamil K. Gebis; Anika P. Wilen; Bian Liu; Richard Johnson; Austin Graves; Tatjana Tchumatchenko; Jeffrey N. Savas; Eugenio F. Fornasiero; Richard L. Huganir; Paul W. Tillberg; Luke D. Lavis; Karel Svoboda; Nelson Spruston

doi:10.1038/s41593-025-01923-4

DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning

Boaz Mohar^*, Gabriela Michel, Yi Zhi Wang, Veronica Hernandez, Jonathan B. Grimm, Jin Yong Park, Ronak Patel, Morgan Clarke, Timothy A. Brown, Cornelius Bergmann, Kamil K. Gebis, Anika P. Wilen, Bian Liu, Richard Johnson, Austin Graves, Tatjana Tchumatchenko, Jeffrey N. Savas, Eugenio F. Fornasiero, Richard L. Huganir, Paul W. TillbergLuke D. Lavis, Karel Svoboda, Nelson Spruston

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.

Original language	English (US)
Article number	e34202
Pages (from-to)	1089-1098
Number of pages	10
Journal	Nature neuroscience
Volume	28
Issue number	5
DOIs	https://doi.org/10.1038/s41593-025-01923-4
State	Published - May 2025

Funding

We thank C.G. for the generation of the GluA2\u2013HT and the MeCP2\u2013HT lines; B. Foster, M. Copeland, A. Hu and S. Michael for histology; M. DeSantis and D. Alcor for help with imaging; G. Harris, M. Rose and S. Lindo for help with animal husbandry and surgery; A. Gutu, K. Ritola and H. A. Yi for viral reagents; A. Tkachuk, A. Osowski and K. Holland for help with JF-HTL dyes; E. Schreiter for the GFP-HT virus; J. Liu for the MeCP2\u2013HT mouse; and S. Grant for the PSD-95\u2013HT mouse. We thank A. Singh for assistance with dye ligand clearance imaging. We thank the Proteomics Core at Northwestern University for their help with the MS measurements. This research was funded by the Howard Hughes Medical Institute (to B.M., G.M., V.H., J.B.G., J.Y.P., R.P., M.C., T.A.B., P.W.T., L.D.L., K.S. and N.S.), the PGA Foundation (to K.S.), CZI Collaborative Pairs Pilot Project Awards (cycle 2; phase 1; to E.F.F.), SFB1286 (to E.F.F.), the National Institutes of Health Grant S10 OD032464 (to J.N.S.) and European Research Council grant MolDynForSyn number 945700 Horizon 2020 (to T.T.).

ASJC Scopus subject areas

General Neuroscience

Access to Document

10.1038/s41593-025-01923-4

Cite this

Mohar, B., Michel, G., Wang, Y. Z., Hernandez, V., Grimm, J. B., Park, J. Y., Patel, R., Clarke, M., Brown, T. A., Bergmann, C., Gebis, K. K., Wilen, A. P., Liu, B., Johnson, R., Graves, A., Tchumatchenko, T., Savas, J. N., Fornasiero, E. F., Huganir, R. L., ... Spruston, N. (2025). DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning. Nature neuroscience, 28(5), 1089-1098. Article e34202. https://doi.org/10.1038/s41593-025-01923-4

@article{4d51e1984da24da1a6a625f7642d5ab0,

title = "DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning",

abstract = "Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.",

author = "Boaz Mohar and Gabriela Michel and Wang, \{Yi Zhi\} and Veronica Hernandez and Grimm, \{Jonathan B.\} and Park, \{Jin Yong\} and Ronak Patel and Morgan Clarke and Brown, \{Timothy A.\} and Cornelius Bergmann and Gebis, \{Kamil K.\} and Wilen, \{Anika P.\} and Bian Liu and Richard Johnson and Austin Graves and Tatjana Tchumatchenko and Savas, \{Jeffrey N.\} and Fornasiero, \{Eugenio F.\} and Huganir, \{Richard L.\} and Tillberg, \{Paul W.\} and Lavis, \{Luke D.\} and Karel Svoboda and Nelson Spruston",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = may,

doi = "10.1038/s41593-025-01923-4",

language = "English (US)",

volume = "28",

pages = "1089--1098",

journal = "Nature neuroscience",

issn = "1097-6256",

publisher = "Nature Research",

number = "5",

}

Mohar, B, Michel, G, Wang, YZ, Hernandez, V, Grimm, JB, Park, JY, Patel, R, Clarke, M, Brown, TA, Bergmann, C, Gebis, KK, Wilen, AP, Liu, B, Johnson, R, Graves, A, Tchumatchenko, T, Savas, JN, Fornasiero, EF, Huganir, RL, Tillberg, PW, Lavis, LD, Svoboda, K & Spruston, N 2025, 'DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning', Nature neuroscience, vol. 28, no. 5, e34202, pp. 1089-1098. https://doi.org/10.1038/s41593-025-01923-4

TY - JOUR

T1 - DELTA

T2 - a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning

AU - Mohar, Boaz

AU - Michel, Gabriela

AU - Wang, Yi Zhi

AU - Hernandez, Veronica

AU - Grimm, Jonathan B.

AU - Park, Jin Yong

AU - Patel, Ronak

AU - Clarke, Morgan

AU - Brown, Timothy A.

AU - Bergmann, Cornelius

AU - Gebis, Kamil K.

AU - Wilen, Anika P.

AU - Liu, Bian

AU - Johnson, Richard

AU - Graves, Austin

AU - Tchumatchenko, Tatjana

AU - Savas, Jeffrey N.

AU - Fornasiero, Eugenio F.

AU - Huganir, Richard L.

AU - Tillberg, Paul W.

AU - Lavis, Luke D.

AU - Svoboda, Karel

AU - Spruston, Nelson

PY - 2025/5

Y1 - 2025/5

N2 - Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.

AB - Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.

UR - http://www.scopus.com/inward/record.url?scp=105001805133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=105001805133&partnerID=8YFLogxK

U2 - 10.1038/s41593-025-01923-4

DO - 10.1038/s41593-025-01923-4

M3 - Article

C2 - 40164741

AN - SCOPUS:105001805133

SN - 1097-6256

VL - 28

SP - 1089

EP - 1098

JO - Nature neuroscience

JF - Nature neuroscience

IS - 5

M1 - e34202

ER -

DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this