TNF-α Downregulates Inhibitory Neurotransmission through Protein Phosphatase 1-Dependent Trafficking of GABA_AReceptors

Abstract

Inflammation has been implicated in the progression of neurological disease, yet precisely how inflammation affects neuronal function remains unclear. Tumor necrosis factor-␣ (TNF␣) is a proinflammatory cytokine that regulates synapse function by controlling neurotransmitter receptor trafficking and homeostatic synaptic plasticity. Here we characterize the mechanisms through which TNF␣ regulates inhibitory synapse function in mature rat and mouse hippocampal neurons. Acute application of TNF␣ induces a rapid and persistent decrease of inhibitory synaptic strength and downregulation of cell-surface levels of GABA A Rs containing ␣1, ␣2, ␤2/3, and ␥2 subunits. We show that trafficking of GABA A Rs in response to TNF␣ is mediated by neuronally expressed TNF receptor 1 and requires activation of p38 MAPK, phosphatidylinositol 3-kinase, protein phosphatase 1 (PP1), and dynamin GTPase. Furthermore, TNF␣ enhances the association of PP1 with GABA A R ␤3 subunits and dephosphorylates a site on ␤3 known to regulate phospho-dependent interactions with the endocytic machinery. Conversely, we find that calcineurin and PP2A are not essential components of the signaling pathway and that clustering of the scaffolding protein gephyrin is only reduced after the initial receptor endocytosis. Together, these findings demonstrate a distinct mechanism of regulated GABA A R endocytosis that may contribute to the disruption of circuit homeostasis under neuroinflammatory conditions.

A metaplasticity view of the interaction between homeostatic and Hebbian plasticity

“…TNFa is a glial-derived factor that was first described in in vitro studies to be required for homeostatic upscaling of excitatory synaptic transmission and downscaling of inhibitory synaptic transmission, but not involved in Hebbian LTP and LTD [122][123][124][125]. Its role in homeostatic plasticity was further confirmed in vivo, where TNFa knockout mice display typical Hebbian weakening of visual cortical responses following brief MD, but fail to exhibit the normal delayed homeostatic rebound [45].…”

Gephyrin: a central GABAergic synapse organizer

“…43,44 In this context, it seems noteworthy that acute application of tumor necrosis factor-α downregulates inhibitory synaptic transmission via the protein phosphatase 1-dependent trafficking of GABA A receptors. 46 In addition to phosphorylation, gephyrin is subject to palmitoylation 47 (Figure 1). Gephyrin was initially postulated as a potential substrate for palmitoyl acyltransferase, 48 and later work confirmed that cysteine 212 and cysteine 284 are palmitoylated by the enzyme, Asp-His-His-Cys (DHHC)-12, which is localized to the Golgi apparatus and dendritic shaft, and directly interacts with gephyrin.…”

Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores

“…It is based on Ca 2+ -dependent negative feedback mechanisms and aims at adjusting synaptic strength to perturbations in neuronal activity (Turrigiano, 2012;Vitureira et al, 2012;Davis, 2013). If for example network activity is reduced, neurons will respond with a slow adaptive, i.e., homeostatic increase in excitatory synaptic strength (or the compensatory down-scaling of inhibitory synapses; e.g., Pribiag and Stellwagen, 2013;Vlachos et al, 2013c). Likewise, increased network-activity will cause the down-regulation of excitatory synaptic strength and an increase in inhibitory synaptic drive.…”