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

TL;DR

Microglia help form synapses in the nucleus accumbens during early development, influencing adult threat avoidance behaviors.

Contribution

This study reveals a novel role for microglia in synapse formation in the nucleus accumbens during early development.

Findings

Microglial absence reduces excitatory synapse formation in the NAc during postnatal weeks 2-3.

Microglia influence presynaptic release probability and postsynaptic kinetics in the NAc.

Lack of microglia leads to lasting effects on threat avoidance behaviors linked to NAc neuronal activity.

Abstract

While CNS microglia have well-established roles in synapse pruning during neurodevelopment, only a few studies have identified roles for microglia in synapse formation. These studies focused on the cortex and primary sensory circuits during restricted developmental time periods, leaving substantial gaps in our understanding of the early developmental functions of microglia. Here we investigated how the absence of microglia impacts synaptic development in the nucleus accumbens (NAc), a region critical for emotional regulation and motivated behaviors and where dysfunction is implicated in psychiatric disorders that arise early in life. Using a genetically modified mouse that lacks microglia (Csf1rΔFIRE/ΔFIRE), we found blunted excitatory synapse formation in the NAc. This effect was most prominent during the second and third postnatal weeks, when we previously found microglia to be overproduced, and was accompanied by an increase in presynaptic release probability and alterations in postsynaptic kinetics. Tissue-level NAc proteomics confirmed that microglial absence impacted numerous proteins involved in synapse structure, trans-synaptic signaling, and pre-synaptic function. However, microglial absence did not perturb levels of astrocyte-derived cues and adhesive proteins that promote synaptogenesis, suggesting that reduced synapse number may be caused by absence of a microglial-derived synaptogenic cue. Although observed electrophysiological synaptic changes were largely normalized by adulthood, we identified lasting effects of microglial absence on threat avoidance behavior, and these behavioral effects were directly associated with alterations of NAc neuronal activity. Together, these results indicate a critical role for microglia in regulating the synaptic landscape of the developing NAc and in establishing functional circuits underlying adult behavioral repertoires.

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