LPS-induced acute neuroinflammation, involving interleukin-1 beta signaling, leads to proteomic, cellular, and network-level changes in the prefrontal cortex of mice

Abstract

Neuroinflammation induced by peripheral infections leads to various neuropsychiatric symptoms both in humans and laboratory animals, e.g., to the manifestation of sickness behavior that resembles some features of clinical depression. However, in addition to depression-like behavior, there are other symptoms of acute systemic inflammation that can be associated with the impairment of prefrontal cortex (PFC)-regulated cognitive functions. Thus, we investigated the electrophysiological and proteomic alterations of the PFC using brain slices and the lipopolysaccharide (LPS) model of acute peripheral infection in male mice. Based on the gene expression differences of the coreceptor ( Il1rap) of interleukin-1 beta (IL-1β) between neuron types in our previous single-cell sequencing dataset, we first compared the electrophysiological effects of IL-1β on PFC pyramidal cells and interneurons. We found that pyramidal cells are more responsive to IL-1β, as could be presumed from our transcriptomic data. To examine the possible circuit-level correlates of the cellular changes, frontal electroencephalographic (EEG) activity and fronto-occipital functional connectivity were analyzed in LPS-treated mice and significant changes were found in the fronto-occipital EEG correlation and coherence in the delta and high-gamma frequency bands. The upregulation of the prefrontal IL-1 system (IL-1β and its receptor) after LPS treatment was revealed by immunoassays simultaneously with the observed EEG changes. Furthermore, we investigated the LPS-induced alterations of the synaptic proteome in the PFC using 2-D differential gel electrophoresis and mass spectrometry and found 48 altered proteins mainly related to cellular signaling, cytoskeletal organization, and carbohydrate/energy metabolism. Thus, our results indicate remarkable electrophysiological and molecular changes in the PFC related to acute systemic inflammation that may explain some of the concomitant behavioral and physiological symptoms.

Highlights

• •

  The gene of IL-1RAcP is expressed differently by the two major types of PFC neurons.

• •

  IL-1β has different electrophysiological effects on these neurons.

• •

  Peripheral LPS induces changes in fronto-occipital EEG activity and synchrony.

• •

  The upregulation of the IL-1 signaling is simultaneous with the EEG changes.

• •

  LPS challenge leads to functional alterations in the synaptic proteome of the PFC.