Microglia modulate TNFα‐mediated synaptic plasticity

Abstract

The pro-inflammatory cytokine tumor necrosis factor α (TNFα) tunes the capacity of neurons to express synaptic plasticity. It remains, however, unclear how TNFα mediates synaptic positive (=change) and negative (=stability) feedback mechanisms. We assessed effects of TNFα on microglia activation and synaptic transmission onto CA1 pyramidal neurons of mouse organotypic entorhino-hippocampal tissue cultures. TNFα mediated changes in excitatory and inhibitory neurotransmission in a concentration-dependent manner, where low concentration strengthened glutamatergic neurotransmission via synaptic accumulation of GluA1-only-containing AMPA receptors and higher concentration increased inhibition. The latter induced the synaptic accumulation of GluA1-only-containing AMPA receptors as well. However, activated, pro-inflammatory microglia mediated a homeostatic adjustment of excitatory synapses, that is, an initial increase in excitatory synaptic strength at 3 h returned to baseline within 24 h, while inhibitory neurotransmission increased. In microglia-depleted tissue cultures, synaptic strengthening triggered by high levels of TNFα persisted and the impact of TNFα on inhibitory neurotransmission was still observed and dependent on its concentration. These findings underscore the essential role of microglia in TNFα-mediated synaptic plasticity. They suggest that pro-inflammatory microglia mediate synaptic homeostasis, that is, negative feedback mechanisms, which may affect the ability of neurons to express further plasticity, thereby emphasizing the importance of microglia as gatekeepers of synaptic change and stability.

Changes in neuroinflammatory markers and microglial density in the hippocampus and prefrontal cortex of the C58/J mouse model of autism

“…TNF‐α is capable of mediating synaptic upscaling in the hippocampus through increasing the location of AMPA receptors to the neuronal membrane surface while it reduces the number of GABA A receptors (Stellwagen et al, 2005; Stellwagen & Malenka, 2006). Moreover, microglia is necessary for modulating the synaptic upscaling induced by high concentrations of TNF‐α, returning excitatory neurotransmission to baseline by 24 h (Kleidonas et al, 2023). The excess of TNF‐α can also impact synapses negatively by causing excitotoxicity (Stellwagen et al, 2005).…”

Axon morphology and intrinsic cellular properties determine repetitive transcranial magnetic stimulation threshold for plasticity

“…Furthermore, neuromodulators can impact the capacity of neurons to express plasticity without affecting excitability and other baseline functional and structural properties, a phenomenon known as metaplasticity ( Abraham and Bear, 1996 ; Seol et al, 2007 ). It is important to also note that non-neuronal cells can significantly influence the capacity of neurons to express synaptic plasticity ( Stellwagen et al, 2005 ; Henneberger et al, 2010 ; Allen, 2014 ; Andoh and Koyama, 2021 ; Sancho et al, 2021 ; Kleidonas et al, 2023 ). Our prior work has provided evidence that cytokines derived from microglia play a crucial role in facilitating rTMS-induced plasticity ( Eichler et al, 2023 ).…”

Regional Microglial Response in Entorhino–Hippocampal Slice Cultures to Schaffer Collateral Lesion and Metalloproteinases Modulation

“…Entorhinohippocampal slice cultures are particularly valuable in this context as they allow for in vitro investigation while preserving the complex cyto-and fiber architecture of the neuroglial network. This makes them an effective experimental model for studying the morphological, molecular, and functional dynamics of glial cells [22,37,38].…”