Astrocytic TNF-α and the Homeostatic Control of Synaptic Scaling

Homeostatic plasticity operates on a slower timescale than Hebbian plasticity to stabilize neuronal firing rates across a network. Synaptic scaling is a key homeostatic mechanism that globally adjusts synaptic strength in a multiplicative manner, and glial-derived Tumor Necrosis Factor-alpha is a critical mediator of this process.

Under basal conditions, astrocytes constitutively release TNF-α, which maintains a tonic level of surface AMPA receptor expression on neurons. During periods of sustained network silencing, this constitutive release is upregulated. The cytokine signals through its cognate receptor, TNFR1, on the postsynaptic neuron.

The intracellular signaling pathway linking TNFR1 activation to AMPA receptor exocytosis involves the c-Jun N-terminal kinase pathway and the transcription factor NF-κB. This leads to an increased transcription and insertion of GluA2-lacking AMPA receptors into the postsynaptic membrane. These receptors have higher single-channel conductance and are calcium-permeable, resulting in a net scaling up of synaptic strength.

Conversely, prolonged increases in network activity suppress the release of TNF-α from astrocytes. The existing TNF-α protein has a short half-life, and its rapid degradation leads to a decrease in TNFR1 signaling. This results in the endocytosis of AMPA receptors and a concomitant scaling down of synaptic efficacy across all synapses on the neuron.

This bidirectional scaling mechanism is crucial for preventing neural circuits from entering states of hyperactivity or silence. It demonstrates that the traditional neuron-centric view of plasticity is incomplete; astrocytes are active participants in regulating synaptic weight and network stability through cytokine signaling.

Dysregulation of this astrocyte-neuron dialogue is implicated in pathological conditions. In models of epilepsy, disrupted TNF-α signaling can contribute to hyperexcitability. Conversely, in neuroinflammatory states, excessive TNF-α can lead to the pathological pruning of synapses, a feature observed in conditions like major depressive disorder and Alzheimer’s disease, highlighting the delicate balance required for brain health.

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