A brain atlas of synapse protein lifetime across the mouse lifespan

Edita Bulovaite; Zhen Qiu; Maximilian Kratschke; Adrianna Zgraj; David G Fricker; Eleanor J Tuck; Ragini Gokhale; Babis Koniaris; Shekib A Jami; Paula Merino-Serrais; Elodie Husi; Lorena Mendive-Tapia; Marc Vendrell; Thomas J O'Dell; Javier DeFelipe; Noboru H Komiyama; Anthony Holtmaat; Erik Fransén; Seth G N Grant

doi:10.1016/j.neuron.2022.09.009

A brain atlas of synapse protein lifetime across the mouse lifespan

Neuron. 2022 Dec 21;110(24):4057-4073.e8. doi: 10.1016/j.neuron.2022.09.009. Epub 2022 Oct 5.

Authors

Edita Bulovaite¹, Zhen Qiu¹, Maximilian Kratschke¹, Adrianna Zgraj¹, David G Fricker¹, Eleanor J Tuck¹, Ragini Gokhale¹, Babis Koniaris², Shekib A Jami³, Paula Merino-Serrais⁴, Elodie Husi⁵, Lorena Mendive-Tapia⁶, Marc Vendrell⁶, Thomas J O'Dell³, Javier DeFelipe⁴, Noboru H Komiyama⁷, Anthony Holtmaat⁵, Erik Fransén⁸, Seth G N Grant⁹

Affiliations

¹ Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK.
² Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; School of Computing, Edinburgh Napier University, Edinburgh EH10 5DT, UK.
³ Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Integrative Center for Learning and Memory, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Laboratorio Cajal de Circuitos Corticales, Centro de Tecnología Biomédica, UPM, 28223 Madrid, Spain; Instituto Cajal, CSIC, 28002 Madrid, Spain.
⁵ Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
⁶ Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.
⁷ Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK; The Patrick Wild Centre for Research into Autism, Fragile X Syndrome & Intellectual Disabilities, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK; Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh EH8 9XD, UK.
⁸ Department of Computational Science and Technology, School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, 10044 Stockholm, Sweden; Science for Life Laboratory, KTH Royal Institute of Technology, 171 65 Solna, Sweden.
⁹ Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK; Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK. Electronic address: seth.grant@ed.ac.uk.

Abstract

The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.

Keywords: HaloTag; aging; autism; brain development; dendritic spine; postsynaptic density; protein turnover; proteostasis; pyramidal neuron; synapse proteome; synaptome.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / physiology
Disks Large Homolog 4 Protein / metabolism
Longevity*
Mice
Neurons / physiology
Synapses* / physiology

Substances

Disks Large Homolog 4 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding