LPS-induced cortical kynurenic acid and neurogranin-NFAT signaling is associated with deficits in stimulus processing during Pavlovian conditioning

Abstract

The N-Methyl-D-Aspartate receptor (NMDAR) antagonist kynurenic acid (KYNA) and the post-synaptic calmodulin binding protein neurogranin (Nrgn) have been implicated in neurological and neuropsychiatric conditions including Alzheimer's disease and schizophrenia. This study indicates that systemic dual-lipopolysaccharide (LPS) injections increases KYNA in the medial prefrontal cortex (mPFC), which is accompanied with increased phosphorylation of nuclear factor kappa chain of activated B cells (NFκB) and activation of the nuclear factor of activated T- cells (NFAT). Our results also indicate that dual-LPS increases Nrgn phosphorylation and concomitantly reduces phosphorylation of calmodulin kinase-I I (CaMKII). We confirmed that systemic blockade of kynurenine-3 monooxygenase in conjunction with kynurenine administration results in significant increases in Nrgn phosphorylation and a significant reduction of CaMKII phosphorylation in the mPFC. Consequently dual-LPS administration induced significant impairments in stimulus processing during Pavlovian conditioning. Taken together, our study indicates that elevations in KYNA in the mPFC can directly regulate NMDA-Nrgn-CaMKII signaling, suggesting that neuroinflammatory conditions affecting this pathway may be associated with cognitive dysfunction.

Lipopolysaccharide Increases Cortical Kynurenic Acid and Deficits in Reference Memory in Mice

“…These findings are in agreement with previous studies showing brain KP modulation following consecutive LPS administration albeit at a dose established to induce depressive like symptomatology 34 and impaired reward motivated learning. 1,24 Bacterial, viral, and parasitical infections are associated with activation of Toll-like receptors (TLRs) signaling, which can be activated experimentally by LPS. The induction of the KP via TLR activation provides a potential mechanism by which changes in kynurenine metabolism may affect brain development.…”

“…All mice used in this study were age matched at -3 months of age and were cared for as previously described. 1,24 Food and water were available ad libitum, although food was restricted only in mice that underwent Pavlovian conditioning and 8-arm radial maze (8-ARM) testing. Animals were group housed with 5 mice per cage on a 12-hour lights on/off cycle (lights on at 06:00 hours).…”

“…To establish a tone-reward contingency during conditioning, mice were given a random series of CS+ tone cues (65 dB and 0.25 seconds duration; ENV-323HAM, 4500 Hz Sonalert, Med-Associates), paired with delivery of a 10 µL sucrose reward. 24,29 During conditioning, the CS+ was randomly spaced by intervals (2-60 seconds), such that on average, a reward was delivered every 15 seconds. The acquisition of Pavlovian learning was determined by measuring the latency between the CS+ and the subsequent CS+ potentiated magazine entry (CS+ reaction time) that resulted, thereby providing a measurement of stimulus-induced attentional processing.…”

Time and frequency dependent changes in resting state EEG functional connectivity following lipopolysaccharide challenge in rats

“…Furthermore these cytokines, as well as LPS, increase kynurenine metabolism in the brain resulting in activation of the KP [ 76 , 77 ] producing several neuroactive metabolites that modulate glutamatergic neurotransmission [ 8 , 78 ]. Of note, kynurenic acid, a metabolite of the KP pathway, which acts as an endogenous NMDA antagonist [ 8 ], is increased by LPS challenge [ 79 , 80 ]. Thus, the effects of LPS on EEG spectra may primarily be the result of interference with glutamatergic and GABAergic neurotransmission in a temporally dependent manner.…”

Autoimmune Mechanisms of Interferon Hypersensitivity and Neurodegenerative Diseases: Down Syndrome

“…Dysregulation of the kynurenine pathway metabolites is reported to produce free radicals and reactive oxygen species (ROS), which are known to promote inflammation and neurodegeneration [31]. e question as to whether the kynurenine pathway is dysregulated in other neurodegenerative diseases in the absence of DS/T21 is partly answered by studies demonstrating dysregulation of NFAT signaling and T-cell activation from administration of lipopolysaccharide (LPS) to mice [32]. LPS administration is associated with elevations in kynurenic acid in the prefrontal cortex and dysregulation of NMDA signaling with deficits in stimulus processing during classical Pavlovian behavioral conditioning [32], likely due to NMDA receptor antagonism by the kynurenic acid, an endogenous NMDA receptor inhibitor also shown to induce a robust cortical inflammatory response, which may disrupt cortical development [33].…”