Microglia Drive Pockets of Neuroinflammation in Middle Age.

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging.SIGNIFICANCE STATEMENT Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.

The active contribution of OPCs to neuroinflammation is mediated by LRP1.

Oligodendrocyte progenitor cells (OPCs) account for about 5% of total brain and spinal cord cells, giving rise to myelinating oligodendrocytes that provide electrical insulation to neurons of the CNS. OPCs have also recently been shown to regulate inflammatory responses and glial scar formation, suggesting functions that extend beyond myelination. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifaceted phagocytic receptor that is highly expressed in several CNS cell types, including OPCs. Here, we have generated an oligodendroglia-specific knockout of LRP1, which presents with normal myelin development, but is associated with better outcomes in two animal models of demyelination (EAE and cuprizone). At a mechanistic level, LRP1 did not directly affect OPC differentiation into mature oligodendrocytes. Instead, animals lacking LRP1 in OPCs in the demyelinating CNS were characterized by a robust dampening of inflammation. In particular, LRP1-deficient OPCs presented with impaired antigen cross-presentation machinery, suggesting a failure to propagate the inflammatory response and thus promoting faster myelin repair and neuroprotection. Our study places OPCs as major regulators of neuroinflammation in an LRP1-dependent fashion.

Synapse-specific roles for microglia in development: New horizons in the prefrontal cortex.

Dysfunction of both microglia and circuitry in the medial prefrontal cortex (mPFC) have been implicated in numerous neuropsychiatric disorders, but how microglia affect mPFC development in health and disease is not well understood. mPFC circuits undergo a prolonged maturation after birth that is driven by molecular programs and activity-dependent processes. Though this extended development is crucial to acquire mature cognitive abilities, it likely renders mPFC circuitry more susceptible to disruption by genetic and environmental insults that increase the risk of developing mental health disorders. Recent work suggests that microglia directly influence mPFC circuit maturation, though the biological factors underlying this observation remain unclear. In this review, we discuss these recent findings along with new studies on the cellular mechanisms by which microglia shape sensory circuits during postnatal development. We focus on the molecular pathways through which glial cells and immune signals regulate synaptogenesis and activity-dependent synaptic refinement. We further highlight how disruptions in these pathways are implicated in the pathogenesis of neurodevelopmental and psychiatric disorders associated with mPFC dysfunction, including schizophrenia and autism spectrum disorder (ASD). Using these disorders as a framework, we discuss microglial mechanisms that could link environmental risk factors including infections and stress with ongoing genetic programs to aberrantly shape mPFC circuitry.