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Updated: May 30, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia regulate nucleus accumbens synaptic development and circuit function underlying threat avoidance behaviors
Michael W Gongwer1,2,3, Fanny Etienne1, Eric N Moca1
1Department of Physiology, University of California Los Angeles, CA, USA.
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 (Csf1r ΔFIRE/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.
Insights
Microglia are crucial for synapse development in the brain's nucleus accumbens. Their absence impairs excitatory synapse formation, impacting emotional regulation and behavior.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Biology
Background:
- Central nervous system (CNS) microglia are known for synapse pruning during development.
- Microglia's role in synapse formation is less understood, particularly in regions beyond the cortex.
- The nucleus accumbens (NAc) is vital for emotional regulation and motivated behaviors, with early-life dysfunction linked to psychiatric disorders.
Purpose of the Study:
- To investigate the impact of microglial absence on synaptic development in the NAc.
- To understand the role of microglia in the early development of NAc circuits.
- To explore the long-term behavioral consequences of altered NAc synaptic development due to microglial absence.
Main Methods:
- Utilized a genetically modified mouse model lacking microglia (Csf1rΔFIRE/ΔFIRE).
- Examined excitatory synapse formation and electrophysiological properties in the NAc during postnatal development.
- Performed tissue-level proteomics of the NAc to identify affected proteins.
- Assessed threat avoidance behavior in adult mice.
Main Results:
- Absence of microglia led to blunted excitatory synapse formation in the NAc, most pronounced in the second and third postnatal weeks.
- Observed increased presynaptic release probability and altered postsynaptic kinetics in the absence of microglia.
- Proteomics revealed impacts on proteins involved in synapse structure, trans-synaptic signaling, and presynaptic function.
- Microglial absence did not affect astrocyte-derived synaptogenic cues, suggesting a microglial-derived cue is involved.
- While electrophysiological changes normalized by adulthood, lasting behavioral deficits in threat avoidance were observed, linked to altered NAc neuronal activity.
Conclusions:
- Microglia play a critical role in regulating the synaptic landscape of the developing NAc.
- Microglia are essential for establishing functional circuits that underlie adult behavioral repertoires.
- The absence of microglia during development has lasting consequences on behavior, mediated by altered NAc neuronal activity.
