TNFα-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity?

Abstract

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

Molecular and functional interactions between tumor necrosis factor-alpha receptors and the glutamatergic system in the mouse hippocampus: Implications for seizure susceptibility

“…These findings strengthen the emerging evidence that inflammatory mediators modulate excitatory neurotransmission (Beattie et al, 2002;Viviani et al, 2003;Leonoudakis et al, 2004;Stellwagen et al, 2005;Stellwagen and Malenka, 2006;Pickering and O'Connor, 2007;Viviani et al, 2007) and suggest that TNF-alpha and glutamate interactions may play a role in pathological conditions (e.g. seizures, neurodegeneration) characterized by the activation of both systems (Ferguson et al, 2008;Vezzani and Granata, 2005).…”

“…In particular, TNF-alpha released by glia increases synaptic efficacy by enhancing AMPA receptors expression on neuronal surface (Beattie et al, 2002;Leonoudakis et al, 2004;Stellwagen et al, 2005), and possibly by increasing astrocytic glutamate release (Bezzi et al, 2001). Moreover, this cytokine has also been shown to affect synaptic plasticity by inhibiting LTP (Tancredi et al, 1992;Cunningham et al, 1996;Butler et al, 2004) and by mediating synaptic scaling during activity blockade (Stellwagen and Malenka, 2006).…”

Rapid Tumor Necrosis Factor α-Induced Exocytosis of Glutamate Receptor 2-Lacking AMPA Receptors to Extrasynaptic Plasma Membrane Potentiates Excitotoxicity

“…Recent studies suggest an alternate mechanism for the induction of TNF␣-induced neuron death through the rapid TNF␣-induced surface expression of AMPA-type glutamate receptors (AMPARs) (Beattie et al, 2002;Ogoshi et al, 2005;Stellwagen et al, 2005). The precise regulation of AMPAR numbers on the postsynaptic plasma membrane is essential for the control of synaptic efficacy (Carroll et al, 2001;Malinow and Malenka, 2002;Song and Huganir, 2002;Bredt and Nicoll, 2003), but disregulation of their trafficking may contribute to excitotoxic vulnerability (Leonoudakis et al, 2004;Pickering et al, 2005).…”

“…This activity can be observed in cortical neurons (Leonoudakis et al, 2004) as well as in intact spinal cord (Fergusen et al, 2006), suggesting that this is a general response of neurons to TNF␣ and postinjury inflammation across the CNS. Increased TNF␣ levels in the CNS contribute to AMPAR-dependent neuron death (Hermann et al, 2001;Noh et al, 2005), and specific blockade of Ca 2ϩ -permeable AMPARs (CP-AMPARs) prevents excitotoxicity in intact spinal cord (Corona and Tapia, 2007).…”

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

“…The increased production of proinflammatory cytokines and infiltration of peripheral immune cells into the central nervous system (CNS) are closely associated with neuronal damage in the spinal cord and many brain regions (6)(7)(8)(9)(10). Elevation of several cytokines such as TNF-α and IFN-γ precedes infiltration of peripheral immune cells and could have a significant impact on neuronal function (11)(12)(13)(14)(15)(16)(17)(18)(19), potentially contributing to early sensory and cognitive impairments. However, the link between the cytokine elevation and CNS deficits in autoimmune diseases remains unclear.…”