Disrupted Neuroglial Metabolic Coupling after Peripheral Surgery

Abstract

Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction. A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

“…In the present study, we showed that IL-1β and IL-6 levels were significantly increased and lasted for 8 days postsurgery. Our results were consistent with the previous studies [15,22,34], suggesting that the hippocampus is susceptible to neuroinflammation induced by anesthesia and surgery. However, the mechanism by which neuroinflammation leading to cognitive impairments following anesthesia and surgery remains unclear.…”

The impact of damage‐associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body

“…Conditioned plasma was obtained from the blood sampled from anaesthetized rats subjected to tibia surgery (one rat per time point), a procedure adapted from an analogous surgery model on mice (Femenia et al., 2018; Terrando et al., 2013). Blood samples were taken before surgery (control), 1, 3, 6 and 24 h after surgery.…”

Astroglial dysfunctions drive aberrant synaptogenesis in developing brain with lengthy general anesthesia

“…Postoperative cognitive dysfunction (POCD) is a chronic decline in cognitive function also associated with anesthesia/surgery. It was found that POCD was associated with astrocytic decreased Ca 2+ signaling along with enhanced synaptic transmission in the mouse hippocampus (35). The causal relationship between astrocyte and neuron dysfunctions in POCD remains to be established.…”