Microglia cells are macrophages resident in the central nervous system and they become activated in most diseases of the central nervous system such as stroke, multiple sclerosis and Alzheimer’s disease. Under such disease conditions, the activation of microglia is complex and associated with its acquisition of multiple reactive phenotypes that can have consequences that range from neuroprotective to neurotoxic. Microglia express a variety of receptors to detect homeostatic imbalance and/or danger signals within the brain parenchyma. It is widely unknown if nonreactive (surveying) microglia play any role in the neuromodulation and neuronal homeostasis that is central to neurotransmission and excitability under physiological conditions.
To address this issue, University of Heidelberg researchers: Andrea Lewen, Thuy-Truc Ta, Tiziana Cesetti, Jan-Oliver Hollnagel, Ismini E. Papageorgiou and Bruno Chausse and led by Professor Oliver Kann clarified the physiological role of microglia in neuromodulation and neuronal homeostasis in postnatal cortex tissue using a series of pharmacological and cell signaling studies. Their results showed that the pharmacological removal of microglia from postnatal cortex tissue had no effect on neuronal gamma oscillations (30-70 Hz), a reflection of the exact communication between different types of neurons and on extracellular potassium ion dynamics, a reflection of the activities of neurons and astrocytes. The work is published in the Journal of Neuroscience Research.
The German research team found that the expression of usual activation markers such as MHC-II was lacking in microglia as seen in untreated (control) slice cultures. Widely nonreactive and ramified microglia were found to be present in slice cultures and liposomal clodronate effectively depleted these microglia within days. The network of parvalbumin-positive GABAergic interneurons and the hippocampal cytoarchitecture in the microglia-depleted slice cultures were found to be well preserved. In addition, no changes were seen in the morphology of astrocytes stained for glial fibrillary acidic protein.
When the authors exchanged the medium in slice cultures, the levels of the pro-inflammatory cytokines IL-6 and TNF-α and nitric oxide in the culture medium were found to be very low. They then stimulated the slice cultures with either bacterial lipopolysaccharide or the pro-inflammatory cytokine interferon-gamma (IFN-γ) to serve as positive controls for microglial reactivity. These immunological stimuli caused an increase in the release of IL-6, TNF-α and nitric oxide. Specifically, the increases in the cytokines and nitric oxide were noticed to be moderate in comparison to paired stimulation with IFN-γ plus lipopolysaccharide that induced severe inflammatory neurodegeneration mostly mediated by pro-inflammatory and reactive microglia. The moderate increase in the release of IL-6 and TNF-α caused by stimulation with lipopolysaccharide was prevented in microglia-depleted slice cultures. Furthermore, the accumulated low basal level of nitric oxide that was observed in microglia-depleted slice cultures was found to be persistent.
The application of acetylcholine to the slice cultures induced neuronal gamma oscillations sharing features with gamma oscillations in vivo, which usually require both fast rhythmic GABAergic inhibition and glutamatergic excitation. In microglia-depleted slice cultures, the researchers also noticed that gamma oscillations were still present with no differences in the stability, frequency, power, the full width at half maximum and the time constant of the oscillations. Additionally, stimulus-induced [K+]o transients in slice cultures revealed intact K+ homeostasis, neuronal excitability and synaptic transmission which were unchanged in microglia-depleted slice cultures.
Through this study, the authors have provided compelling evidence to support the biological notion that nonreactive (surveying) microglia are not required for signaling, rhythm generation and neuronal homeostasis in the healthy postnatal brain. This evolutionary feature might permit the unrestricted phenotypic flexibility of microglia in response to any homeostatic imbalance and pathology within the central nervous system.
Lewen A, Ta TT, Cesetti T, Hollnagel JO, Papageorgiou IE, Chausse B, Kann O. Neuronal gamma oscillations and activity-dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue. J Neurosci Res. 2020;98(10):1953-1967.Go To J Neurosci Res