Cytokine Signalling at the Microglial Penta-Partite Synapse

Abstract

Microglial cell processes form part of a subset of synaptic contacts that have been dubbed microglial tetra-partite or quad-partite synapses. Since tetrapartite may also refer to the presence of extracellular matrix components, we propose the more precise term microglial penta-partite synapse for synapses that show a microglial cell process in close physical proximity to neuronal and astrocytic synaptic constituents. Microglial cells are now recognised as key players in central nervous system (CNS) synaptic changes. When synaptic plasticity involving microglial penta-partite synapses occurs, microglia may utilise their cytokine arsenal to facilitate the generation of new synapses, eliminate those that are not needed anymore, or modify the molecular and structural properties of the remaining synaptic contacts. In addition, microglia–synapse contacts may develop de novo under pathological conditions. Microglial penta-partite synapses have received comparatively little attention as unique sites in the CNS where microglial cells, cytokines and other factors they release have a direct influence on the connections between neurons and their function. It concerns our understanding of the penta-partite synapse where the confusion created by the term “neuroinflammation” is most counterproductive. The mere presence of activated microglia or the release of their cytokines may occur independent of inflammation, and penta-partite synapses are not usually active in a neuroimmunological sense. Clarification of these details is the main purpose of this review, specifically highlighting the relationship between microglia, synapses, and the cytokines that can be released by microglial cells in health and disease.

Microglia Impairs Proliferation and Induces Senescence In-Vitro in NGF Releasing Cells Used in Encapsulated Cell Biodelivery for Alzheimer’s Disease Therapy

“…This effect was more apparent and prolonged in devices incubated with MCM Aβ40 compared to MCM Aβ42 . It is important to note that even the MCM Untr supernatant also reduced hmNGF release from ECB-NGF devices, indicating that NGC0211 cells are sensitive to factors released by untreated microglia, as previously shown by other reports [ 27 ]. Furthermore, we provided evidence that the activation of the HMC3 cell line with the Aβ40 peptide can contribute to a lower proliferation rate of NGC0211 cells in-vitro.…”

“…HMC3 cells treated with DMSO (0.1% final concentration) provided control for factors released by unstimulated microglia and denoted as MCM Untr . It is well known that, even under physiological conditions, microglia can release different cytokines [ 27 ]. MCM Untr itself serves as an ‘experimental control’ for additional factors, which might be released upon stimulation by activated microglia.…”

Microglia morphophysiological diversity and its implications for the CNS

“…Microglial effects upon neuronal connectivity are also not limited to the developmental stage. In the adult CNS, microglia have been shown to engulf synaptic material in both the healthy brain and in neurodegenerative conditions ( 13 , 75 – 77 ). Early ultrastructural studies described microglia-mediated displacement of synaptic terminals, suggesting that microglia actively participate in synaptic plasticity ( 78 – 80 ).…”

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

“…In addition, microglia can shape synapses by direct contact with them [ 134 ]. Following synaptic injury, microglia tightly associate with dendrites and directly separate pre-synaptic and post-synaptic neurons, a process known as “synaptic stripping” [ 135 ].…”