Tumor necrosis factor affects both excitatory synaptic transmission and excitotoxic neuronal cell death
Michael Beattie (Department of Neuroscience, The Ohio State University)
(March 14, 2003 11:00 AM - 12:00 PM)
This seminar is based on converging evidence from two very different experimental systems that involve glutamate as a neurotransmitter, and as an excitotoxic agent that kills neurons after injury.
Much of the excitatory synaptic transmission in the CNS is mediated by glutamate through post-synaptic receptors that open ion channels in response to glutamate release. Recent evidence suggests that changes in excitability at these synapses such as those that occur in long term depression (LTD) or potentiation (LTP) are due, in part, to rapid changes in the number of receptors located at the synapse due to modulation of receptor recycling.
Extracellular glutamate increases rapidly after injury to the CNS, and very high levels can cause neuronal and glial death by increasing intracellular Ca++ to toxic levels. Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that is released by immune cells and can induce necrotic and apoptotic death in target cells. After injury to the CNS, TNF levels increase markedly, and TNF has been thought to be a possible mediator of secondary cell death after stroke, spinal cord injury (SCI), and also in multiple sclerosis (MS). TNF also seems to increase glutamate actions in a brainstem circuit mediating gastric motility (Emch, Hermann, and Rogers, 2000). We tested the hypothesis that TNF and glutamate might interact after SCI by making nano-injections of TNF or the glutamate agonist kainic acid (KA) into the spinal cord gray matter either alone or together (Hermann et al, 2001). Low doses or either agent produced no cell death; together, they killed large numbers of neurons within 90 minutes. This potentiation of cell death was completely blocked by CNQX, which is an antagonist at AMPA-type glutamate receptors. This suggested that TNF might in some way be altering AMPA-R excitability.
To test this, we engaged the help of collaborators at Stanford and applied TNF to hippocampal neurons in culture (E. Beattie et al, 2002). 15 minutes after application of TNF, AMPARs on the surface of dendrites increased dramatically. Whole cell patch clamp showed a concomitant increase in spontaneous excitatory post-synaptic currents. Reduction of endogenous TNF by antibody treatment reduced AMPAR surface expression and epsc's. Experiments in hippocampal slice also showed a role for TNF in modulating synaptic activity. We showed that changes in extracellular K+ changed both AMPAR surface expression and susceptibility of cerebellar granule cells to excitotoxic cell death (Ha et al, 2002). Thus it appears that modulation of AMPARs by TNF (and other agents) may be involved in both synaptic plasticity (and learning?) and the induction of cell death. There are some therapeutic implications of these findings.