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Published on: June 8, 2014
FcγR- and CD9-dependent synapse engulfing microglia in the thalamus drives cognitive impairment following cortical
Abstract:
Various states of microglia appear in neuroinflammation, but their impact on brain function and behavior is not fully understood. Here we report that synapse engulfing microglia in the thalamus are crucial for cognitive impairment after cortical brain injury. Region-specific manipulations of reactive microglia in the chronic phase of injuries showed that microglial changes in the thalamus, but not in the hippocampus, impaired recognition memory. Single-cell RNA-sequencing analysis revealed the enrichment of synapse engulfing microglia in the thalamus, which developed in a CD9-dependent manner and caused synaptic loss and recognition memory deficits. In the thalamus, the blood-brain barrier was disrupted, and extravasated γ-immunoglobulins (IgG) co-localized with synapse engulfing microglia. Fc γ receptor III blockade in the thalamus reduced synapse engulfing microglia, synapse loss, and recognition memory deficits. These findings demonstrate that the induction of synapse engulfing microglia in the thalamus by extravasated IgG/Fc γ RIII and CD9 signals causes recognition memory deficits after cortical brain injury.
Insights
Synapse engulfing microglia in the thalamus drive cognitive deficits after brain injury. Blocking Fc gamma receptor III in the thalamus restores memory, highlighting a therapeutic target for brain injury recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia play diverse roles in neuroinflammation, but their specific impact on cognitive function remains unclear.
- Understanding microglial states and their regional effects is crucial for addressing brain dysfunction after injury.
Purpose of the Study:
- To investigate the role of specific microglial states in cognitive impairment following cortical brain injury.
- To identify the mechanisms underlying microglial involvement in memory deficits.
Main Methods:
- Region-specific manipulation of microglia in rodent models of cortical brain injury.
- Single-cell RNA-sequencing to characterize microglial populations.
- Immunohistochemistry to analyze microglial-synapse interactions and blood-brain barrier integrity.
- Pharmacological blockade of Fc gamma receptor III (FcγRIII).
Main Results:
- Microglial changes in the thalamus, not the hippocampus, were linked to impaired recognition memory.
- Synapse engulfing microglia were enriched in the thalamus, dependent on CD9 signaling, leading to synaptic loss.
- Disruption of the blood-brain barrier allowed extravasated immunoglobulins (IgG) to co-localize with these microglia.
- FcγRIII blockade reduced synapse engulfing microglia, synaptic loss, and memory deficits.
Conclusions:
- Synapse engulfing microglia in the thalamus are critical mediators of cognitive impairment after cortical injury.
- Extravasated IgG binding to FcγRIII and CD9 signaling induce these detrimental microglia.
- Targeting FcγRIII in the thalamus presents a potential therapeutic strategy for improving memory outcomes post-brain injury.
