Synaptic Pruning Through Glial Synapse Engulfment Upon Motor Learning

Overview

Journal Nat Neurosci

Date 2022 Nov 2

PMID 36319770

Authors

Yosuke M Morizawa

Mami Matsumoto

Yuka Nakashima

Narumi Endo

Tomomi Aida

Hiroshi Ishikane

Kaoru Beppu

Satoru Moritoh

Hitoshi Inada

Noriko Osumi

Eiji Shigetomi

Schuichi Koizumi

Guang Yang

Hirokazu Hirai

Kohichi Tanaka

Kenji F Tanaka

Nobuhiko Ohno

Yugo Fukazawa

Ko Matsui

Affiliations

Soon will be listed here.

Abstract

Synaptic pruning is a fundamental process of neuronal circuit refinement in learning and memory. Accumulating evidence suggests that glia participates in sculpting the neuronal circuits through synapse engulfment. However, whether glial involvement in synaptic pruning has a role in memory formation remains elusive. Using newly developed phagocytosis reporter mice and three-dimensional ultrastructural characterization, we found that synaptic engulfment by cerebellar Bergmann glia (BG) frequently occurred upon cerebellum-dependent motor learning in mice. We observed increases in pre- and postsynaptic nibbling by BG along with a reduction in spine volume after learning. Pharmacological blockade of engulfment with Annexin V inhibited both the spine volume reduction and overnight improvement of motor adaptation. These results indicate that BG contribute to the refinement of the mature cerebellar cortical circuit through synaptic engulfment during motor learning.

Citing Articles

Is the Relationship Between Adolescent Social Isolation and Anxiety-Like Behaviors Altered by Microglia Ablation in Female Long Evans Rats?.

Blumberg M, Shipman A, Olyha L, Gironda S, Weiner J Brain Behav. 2025; 15(3):e70369.

PMID: 40059451 PMC: 11891277. DOI: 10.1002/brb3.70369.

Cognitive, Neurophysiological, and Behavioral Adaptations in Golf Putting Motor Learning: A Holistic Approach.

Abdoli N, Saberi Kakhki A, Taheri Torbati H, Ghoshuni M, Schack T Psychol Res. 2025; 89(2):59.

PMID: 40024952 DOI: 10.1007/s00426-025-02091-7.

Nrf2 Ameliorates Sevoflurane-Induced Cognitive Deficits in Aged Mice by Inhibiting Neuroinflammation in the Hippocampus.

Li J, Li J, Liu Y, Hu C, Xu H, Cao D Mol Neurobiol. 2025; .

PMID: 39969679 DOI: 10.1007/s12035-025-04777-w.

Axonal Selectivity of Myelination by Single Oligodendrocytes Established During Development in Mouse Cerebellar White Matter.

Battulga B, Osanai Y, Yamazaki R, Shinohara Y, Ohno N Glia. 2024; 73(4):873-886.

PMID: 39688302 PMC: 11845844. DOI: 10.1002/glia.24660.

CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles of in microglia endocytosis and synaptic pruning.

Teter O, McQuade A, Hagan V, Liang W, Drager N, Sattler S bioRxiv. 2024; .

PMID: 39605704 PMC: 11601228. DOI: 10.1101/2024.06.01.596962.

References

Holtmaat A, Svoboda K . Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009; 10(9):647-58. DOI: 10.1038/nrn2699. View

Caroni P, Donato F, Muller D . Structural plasticity upon learning: regulation and functions. Nat Rev Neurosci. 2012; 13(7):478-90. DOI: 10.1038/nrn3258. View

Forrest M, Parnell E, Penzes P . Dendritic structural plasticity and neuropsychiatric disease. Nat Rev Neurosci. 2018; 19(4):215-234. PMC: 6442683. DOI: 10.1038/nrn.2018.16. View

Kasai H, Ziv N, Okazaki H, Yagishita S, Toyoizumi T . Spine dynamics in the brain, mental disorders and artificial neural networks. Nat Rev Neurosci. 2021; 22(7):407-422. DOI: 10.1038/s41583-021-00467-3. View

Ito M . Long-term depression. Annu Rev Neurosci. 1989; 12:85-102. DOI: 10.1146/annurev.ne.12.030189.000505. View

Boyden E, Katoh A, Raymond J . Cerebellum-dependent learning: the role of multiple plasticity mechanisms. Annu Rev Neurosci. 2004; 27:581-609. DOI: 10.1146/annurev.neuro.27.070203.144238. View

Kano M, Rexhausen U, Dreessen J, Konnerth A . Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells. Nature. 1992; 356(6370):601-4. DOI: 10.1038/356601a0. View

Schonewille M, Belmeguenai A, Koekkoek S, Houtman S, Boele H, van Beugen B . Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron. 2010; 67(4):618-28. PMC: 2941980. DOI: 10.1016/j.neuron.2010.07.009. View

Kim Y, Kim S . Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice. Mol Brain. 2020; 13(1):136. PMC: 7542746. DOI: 10.1186/s13041-020-00678-2. View

10.

Gutierrez-Castellanos N, Da Silva-Matos C, Zhou K, Canto C, Renner M, Koene L . Motor Learning Requires Purkinje Cell Synaptic Potentiation through Activation of AMPA-Receptor Subunit GluA3. Neuron. 2017; 93(2):409-424. PMC: 5263704. DOI: 10.1016/j.neuron.2016.11.046. View

11.

Wang W, Nakadate K, Masugi-Tokita M, Shutoh F, Aziz W, Tarusawa E . Distinct cerebellar engrams in short-term and long-term motor learning. Proc Natl Acad Sci U S A. 2013; 111(1):E188-93. PMC: 3890858. DOI: 10.1073/pnas.1315541111. View

12.

Aziz W, Wang W, Kesaf S, Mohamed A, Fukazawa Y, Shigemoto R . Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning. Proc Natl Acad Sci U S A. 2013; 111(1):E194-202. PMC: 3890840. DOI: 10.1073/pnas.1303317110. View

13.

Inoshita T, Hirano T . Occurrence of long-term depression in the cerebellar flocculus during adaptation of optokinetic response. Elife. 2018; 7. PMC: 5871328. DOI: 10.7554/eLife.36209. View

14.

Kakegawa W, Katoh A, Narumi S, Miura E, Motohashi J, Takahashi A . Optogenetic Control of Synaptic AMPA Receptor Endocytosis Reveals Roles of LTD in Motor Learning. Neuron. 2018; 99(5):985-998.e6. DOI: 10.1016/j.neuron.2018.07.034. View

15.

Chung W, Clarke L, Wang G, Stafford B, Sher A, Chakraborty C . Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013; 504(7480):394-400. PMC: 3969024. DOI: 10.1038/nature12776. View

16.

Schafer D, Lehrman E, Kautzman A, Koyama R, Mardinly A, Yamasaki R . Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012; 74(4):691-705. PMC: 3528177. DOI: 10.1016/j.neuron.2012.03.026. View

17.

Hong S, Beja-Glasser V, Nfonoyim B, Frouin A, Li S, Ramakrishnan S . Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016; 352(6286):712-716. PMC: 5094372. DOI: 10.1126/science.aad8373. View

18.

Morizawa Y, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y . Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun. 2017; 8(1):28. PMC: 5481424. DOI: 10.1038/s41467-017-00037-1. View

19.

Lee J, Kim J, Noh S, Lee H, Lee S, Mun J . Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature. 2020; 590(7847):612-617. DOI: 10.1038/s41586-020-03060-3. View

20.

Chung W, Verghese P, Chakraborty C, Joung J, Hyman B, Ulrich J . Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016; 113(36):10186-91. PMC: 5018780. DOI: 10.1073/pnas.1609896113. View