Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors in mice

While microglia are well known for pruning synapses during neurodevelopment, their role in synapse formation remains understudied. Here we investigate how microglial absence impacts synaptic development in the nucleus accumbens (NAc), a region critical for emotional regulation and motivated behaviors. Using genetically modified mice lacking microglia (Csf1rΔFIRE/ΔFIRE), we find blunted excitatory synapse formation in the NAc, particularly during the second and third postnatal weeks.

Tissue-level NAc proteomics in the third postnatal week reveals changes in proteins involved in synapse structure, trans-synaptic signaling, and pre-synaptic function. Although electrophysiological changes largely resolve by adulthood, microglia-lacking mice exhibit persistent changes in threat avoidance behavior and underlying NAc neuronal activity. Transient depletion of NAc microglia during the second postnatal week similarly disrupts synapse formation and adult threat avoidance.

Together, these findings identify a role for microglia in shaping NAc synaptic development and in establishing functional circuits that support adult behavioral function. We thank the UCLA Proteome Research Center and J. Jami-Alahmadi for their assistance with tissue proteomics.

This work was supported by R01MH127214 (L.A.D.), Vallee Scholars Award (L.A.D.), Brain and Behavior Research Foundation NARSAD Young Investigator Award (L.M.D.), Brain Research Foundation Seed Grant (L.M.D.), UCLA David Geffen School of Medicine Seed Grant (L.A.D., L.M.D), F30MH134633 (M.W.G.), T32GM008042 (M.W.G.), T32NS048004 (M.W.G.), Jessamine Hilliard Award (S.V.B.), NSF Graduate Research Fellowships (M.S.C. and K.A.N.). These authors contributed equally: Michael W. Department of Physiology, University of California, Los Angeles, CA, USA Michael W.

Gongwer, Fanny Etienne, Eric N. Blagburn-Blanco, Megan S. Christensen, Alexander S.

Enos, Melody Haratian, Laura A. De Biase Neuroscience Interdepartmental Program, University of California, Los Angeles, CA, USA Michael W. Newton UCLA Medical Scientist Training Program, University of California, Los Angeles, CA, USA Michael W.