Abstract
The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO.
Highlights
Tumor necrosis factor-α (TNFα) is a pleiotropic cytokine suspected to enhance or deter cellular survival through activation of receptor-mediated signal transduction
Field potentials were examined in CA1 stratum radiatum of hippocampal slices obtained from naïve TNFα-Tg rats and non-Tg littermates (n = 6–8 per group) that did not undergo focal cerebral ischemia
Pairedpulse facilitation (PPF), a transient form of synaptic plasticity, and long-term potentiation (LTP), a long-lasting form of plasticity, were both increased by a similar extent in TNFα Tg rats (Fig 1B–1D)
Summary
Tumor necrosis factor-α (TNFα) is a pleiotropic cytokine suspected to enhance or deter cellular survival through activation of receptor-mediated signal transduction. The level of TNFα in human brain becomes elevated after cerebral infarction [5] and appears sequentially in the infarct core and peri-infarct areas before expression in tissue within the unaffected. Elevated levels of TNFα have been observed consistently in serum [7,8,9] and in cerebrospinal fluid [8, 9] after acute ischemic stroke. In animal models of cerebral ischemia, high levels of TNFα have been found after global [10, 11] and focal [12] ischemic injury. AntiTNFα antibodies have been shown to be neuroprotective and may reduce infarct volume in focal ischemic models by as much as 85% [13, 17, 18]
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