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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates

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Rod-shaped microglia interact with neuronal dendrites to attenuate cortical excitability during TDP-43-related

Manling Xie1, Yue Liang2, Alessandra S Miller1

  • 1Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Immunity
|September 20, 2025
PubMed

Insights

Rod-shaped microglia protect against neurodegeneration by reducing brain cell overactivity. This study identifies a specific microglial subtype that lessens cortical hyperexcitability in TAR DNA-binding protein 43 (TDP-43) related neurodegeneration.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia are key immune cells in the central nervous system, involved in neuronal activity regulation.
  • Microglial activation is common in neurodegeneration, but their role in disease-related cortical excitability is unclear.

Purpose of the Study:

  • To investigate the specific role of microglia in cortical excitability during TAR DNA-binding protein 43 (TDP-43) neurodegeneration.
  • To identify microglial subtypes involved in regulating neuronal activity in this disease model.

Main Methods:

  • Multichannel probe recordings and longitudinal in vivo calcium imaging in a TDP-43 neurodegeneration mouse model (rNLS8).
  • Spatial and single-cell RNA sequencing to characterize microglial populations.
  • Analysis of the impact of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) deficiency.

Main Results:

  • Neuronal hyperactivity was observed at the early stage of TDP-43 neurodegeneration.
  • A specific subpopulation, rod-shaped microglia, directly responded to cortical hyperactivity.
  • Rod-shaped microglia interacted with neuronal dendrites, remodeling synapses to reduce motor cortical hyperactivity.
  • TREM2 deficiency reduced rod-shaped microglia and increased neuronal activity.

Conclusions:

  • Rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in TDP-43-related neurodegeneration.
  • These findings highlight a specific microglial function in mitigating disease-associated neuronal dysfunction.
Keywords:
TDP-43Trem2amyotrophic lateral sclerosiscortical hyperactivityglial biologymotor neuron diseaseneurodegenerationneuroimmunologyrod-shaped microglia

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