Microglia Promote Learning-dependent Synapse Formation Through Brain-derived Neurotrophic Factor

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Dec 24

PMID 24360280

Citations 1263

Authors

Christopher N Parkhurst

Guang Yang

Ipe Ninan

Jeffrey N Savas

John R Yates 3rd

Juan J Lafaille

Barbara L Hempstead

Dan R Littman

Wen-Biao Gan

Affiliations

Soon will be listed here.

Abstract

Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.

Citing Articles

Biosafety and mental health: Virus induced cognitive decline.

Du C, Li G, Han G Biosaf Health. 2025; 5(3):159-167.

PMID: 40078510 PMC: 11895046. DOI: 10.1016/j.bsheal.2023.04.002.

Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization.

Zhao S, Wang L, Kleidonas D, Qi F, Liang Y, Zheng J Sci Adv. 2025; 11(9):eado7829.

PMID: 40020068 PMC: 11870068. DOI: 10.1126/sciadv.ado7829.

Transcriptomic Analysis Divulges Differential Expressions of Microglial Genes After Microglial Repopulation in Mice.

Hafeez M, Gao H, Ju F, Qi F, Li T, Zhang S Int J Mol Sci. 2025; 26(4).

PMID: 40003960 PMC: 11855859. DOI: 10.3390/ijms26041494.

Brain-Derived Neurotrophic Factor (BDNF) as a Marker of Physical Exercise or Activity Effectiveness in Fatigue, Pain, Depression, and Sleep Disturbances: A Scoping Review.

Lukkahatai N, Ong I, Benjasirisan C, Saligan L Biomedicines. 2025; 13(2).

PMID: 40002745 PMC: 11853410. DOI: 10.3390/biomedicines13020332.

The ontogeny of mouse salivary gland macrophages is distinct between genders.

Zhao Q, Jaiswal J, Chang E, Shahsavari A, Zhang Y, Yu V Res Sq. 2025; .

PMID: 39975913 PMC: 11838738. DOI: 10.21203/rs.3.rs-5903499/v1.

References

Chen N, Luo T, Raymond L . Subtype-dependence of NMDA receptor channel open probability. J Neurosci. 1999; 19(16):6844-54. PMC: 6782868. View

Grutzendler J, Kasthuri N, Gan W . Long-term dendritic spine stability in the adult cortex. Nature. 2002; 420(6917):812-6. DOI: 10.1038/nature01276. View

Ajami B, Bennett J, Krieger C, Tetzlaff W, Rossi F . Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007; 10(12):1538-43. DOI: 10.1038/nn2014. View

Buch T, Heppner F, Tertilt C, Heinen T, Kremer M, Wunderlich F . A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat Methods. 2005; 2(6):419-26. DOI: 10.1038/nmeth762. View

Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E . Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci. 2012; 32(43):15106-11. PMC: 6704837. DOI: 10.1523/JNEUROSCI.1167-12.2012. View

Jung S, Aliberti J, Graemmel P, Sunshine M, Kreutzberg G, Sher A . Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000; 20(11):4106-14. PMC: 85780. DOI: 10.1128/MCB.20.11.4106-4114.2000. View

Chao M . Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci. 2003; 4(4):299-309. DOI: 10.1038/nrn1078. View

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

Swinnen N, Smolders S, Avila A, Notelaers K, Paesen R, Ameloot M . Complex invasion pattern of the cerebral cortex bymicroglial cells during development of the mouse embryo. Glia. 2012; 61(2):150-63. DOI: 10.1002/glia.22421. View

10.

Rauskolb S, Zagrebelsky M, Dreznjak A, Deogracias R, Matsumoto T, Wiese S . Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. J Neurosci. 2010; 30(5):1739-49. PMC: 6633992. DOI: 10.1523/JNEUROSCI.5100-09.2010. View

11.

Peri F, Nusslein-Volhard C . Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell. 2008; 133(5):916-27. DOI: 10.1016/j.cell.2008.04.037. View

12.

Paolicelli R, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P . Synaptic pruning by microglia is necessary for normal brain development. Science. 2011; 333(6048):1456-8. DOI: 10.1126/science.1202529. View

13.

Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R . Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol Endocrinol. 2001; 15(10):1748-57. DOI: 10.1210/mend.15.10.0706. View

14.

Balkowiec A, Katz D . Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ. J Neurosci. 2000; 20(19):7417-23. PMC: 6772775. View

15.

Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V . Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet. 2000; 25(3):357-61. DOI: 10.1038/77153. View

16.

Butko M, Savas J, Friedman B, Delahunty C, Ebner F, Yates 3rd J . In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation. Proc Natl Acad Sci U S A. 2013; 110(8):E726-35. PMC: 3581967. DOI: 10.1073/pnas.1300424110. View

17.

Trang T, Beggs S, Wan X, Salter M . P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci. 2009; 29(11):3518-28. PMC: 3589565. DOI: 10.1523/JNEUROSCI.5714-08.2009. View

18.

Spencer-Segal J, Waters E, Bath K, Chao M, McEwen B, Milner T . Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage. J Neurosci. 2011; 31(18):6780-90. PMC: 3108038. DOI: 10.1523/JNEUROSCI.0910-11.2011. View

19.

Luche H, Weber O, Rao T, Blum C, Fehling H . Faithful activation of an extra-bright red fluorescent protein in "knock-in" Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol. 2006; 37(1):43-53. DOI: 10.1002/eji.200636745. View

20.

Zheng K, An J, Yang F, Xu W, Xu Z, Wu J . TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus. Proc Natl Acad Sci U S A. 2011; 108(41):17201-6. PMC: 3193255. DOI: 10.1073/pnas.1114241108. View