The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

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.

Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons

“…Unlike previous study showing high-dose TNF-α treatment increased basal synaptic transmission in rat hippocampal slices [15], we found TNF-α treatment at a relatively low concentration did not significantly influence either basal synaptic transmission or presynaptic function in the Schaffer collateral pathway of rabbit hippocampus, which is in line with a recent report showing TNF-α did not affect the baseline synaptic transmission at Schaffer collateral-CA1 synapse in mice [88] and in 8-week-old transgenic rats that overexpress a murine TNFα gene [89]. This suggests a presynaptic mechanism via the regulation of presynaptic transmitter release may be not the main contributor to TNF-α induced electrophysiological alterations in rabbit hippocampus, Therefore, the effects of TNF-α on basal neural transmission and presynaptic function may be partly attributed to neuronal toxicity and hyper-excitability induced by a large dose of TNF-α [15, 90] and may be brain region specific [74] or tissue specific [91].…”

“…This is also supported by other studies showing a soluble TNF-α inhibitor can rescue impaired LTP in 5xFAD mice [96] and systemic inflammation impaired LTP at mouse Schaffer collateral-CA1 synapses [97]. However, there are also some contradictory reports showing an increased LTP in transgenic rats that overexpress a murine TNF-α gene [89] and enhanced excitatory field potentials in hippocampal CA 1 stratum radiatum from rat colonic inflammation induced by 2,4,6-trinitrobenzenesulfaonic acid [98] and mouse peritoneal inflammation [99]. These suggest the effects of TNF-α on the central nervous system may be bidirectional and this complexity may depend on many factors including dose [75, 100], exposure duration [75, 100], distribution of different TNF-α receptors among different tissues and cells [63], and the cross-talk between signaling pathways initiated by TNF-α receptor 1 and receptor 2 [64].…”

Tumor Necrosis Factor and Interleukin-1β Modulate Synaptic Plasticity during Neuroinflammation

“…Interestingly, pretreatment of hippocampal slices with TNF after hypoxia improved LTP in the DG [ 59 ]. In line with this, by means of transgenic mice overexpressing TNF, other researchers have demonstrated that chronic exposure to TNF potentiates LTP in CA1 region [ 60 ] (Figures 1(b) and 2(b) ).…”

The role of cytokines in modulating learning and memory and brain plasticity

“…Indeed, studies using 30-day-old mice overexpressing TNF-α did not find any learning and memory impairment in the water maze test ( Aloe et al, 1999 ; Fiore et al, 1996 ), whereas older mice showed impaired memory in a passive avoidance task ( Fiore et al, 1996 ), in the water maze ( Bjugstad et al., 1998 ) and in a three-panel runway task ( Matsumoto et al., 2002 ). Adult rats chronically overexpressing five times the normal levels of murine neuronal TNF-α also display spatial memory impairments in a water maze paradigm ( Pettigrew et al, 2008 , 2016 ). In these animals, hippocampal synaptic plasticity measured by LTP and paired-pulse facilitation are comparable to those measured in the immature hippocampus of neonates, which support a role of TNF-α in maturation of the synaptic network ( Pettigrew et al, 2008 , 2016 ).…”