Peripheral Inflammation Limits Serotonin Neuron Signaling Capacity via Serotonergic IL-1R1 to Reduce Neuronal Excitability and Enhance Serotonin Clearance

Gajewski, P. A.; Iwamoto, H.; Tillman, A. N.; Filliben, Z.; Walsh, A. E.; Baganz, N. L.; Robson, M. J.; Zapata, M.; Quan, N.; Blakely, R. D.

doi:10.1101/2025.10.13.682078

bioRxiv · 10.1101/2025.10.13.682078

Peripheral Inflammation Limits Serotonin Neuron Signaling Capacity via Serotonergic IL-1R1 to Reduce Neuronal Excitability and Enhance Serotonin Clearance

Gajewski, P. A.·Iwamoto, H.·Tillman, A. N.·Filliben, Z.·Walsh, A. E.·Baganz, N. L.·Robson, M. J.·Zapata, M.·Quan, N.·Blakely, R. D.

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Abstract

Neurobehavioral disorders, ranging from depression to schizophrenia, have been found to display immune system alterations. The high incidence of comorbidity of these disorders, particularly depression, with chronic inflammatory conditions suggests shared mechanisms contributing to the manifestation of these conditions. We have previously shown that peripheral modulation of the innate immune system in mice rapidly triggers enhanced serotonin (5-HT) clearance in vivo associated with increased anxiety- and despair-like behaviors that can be suppressed by serotonergic elimination of p38 MAPK. Forebrain-projecting 5-HT synthesizing neurons of the dorsal raphe nucleus (DRN5-HT) play a key role in regulating behaviors related to mood and anxiety and whose perturbations are observed in multiple affective disorders. Here we identify molecular and circuit-level mechanisms that can translate peripheral innate immune system activation into changes in 5-HT signaling capacity. Using whole cell patch clamp recordings from acute midbrain slices, we demonstrate that the proinflammatory cytokine, IL-1{beta}, acts cell autonomously through its receptor, IL-1R1, via the p38 MAPK signaling pathway to rapidly inhibit firing of DRN5-HT neurons. In the dorsal hippocampus, we found that as with acute, peripheral lipopolysaccharide (LPS) administration, local injections of IL-1{beta} rapidly enhance 5-HT clearance as assessed by in vivo chronoamperometry. Like IL-1{beta}, TNF also acts via a serotonergic p38 MAPK dependent pathway to reduce excitability of DRN5-HT neurons. Immunocytochemical studies reveal that, IL-1R1, is nonuniformly expressed by DRN5-HT neurons and is required for LPS-induced inhibition of these cells as detected by cFos activation, with sex-dependent patterns evident. Moreover, we detected both DRN5-HT IL-1R1-dependent and -independent LPS-mediated changes in cFos changes in forbrain projection areas. Our findings support a growing appreciation that serotoninergic neurons contribute to changes in CNS physiology and behavior following peripheral immune activation. More specifically, our studies attest to a functional role of serotonergic IL-1R1 in mediating IL-1{beta} following peripheral innate immune activation, effects likely to arise both from changes in diminished 5-HT neuron excitability and elevated 5-HT clearance.

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Gajewski, P. A., Iwamoto, H., Tillman, A. N., Filliben, Z., Walsh, A. E., Baganz, N. L., Robson, M. J., Zapata, M., Quan, N., Blakely, R. D.. 2025-10-14. Peripheral Inflammation Limits Serotonin Neuron Signaling Capacity via Serotonergic IL-1R1 to Reduce Neuronal Excitability and Enhance Serotonin Clearance. https://doi.org/10.1101/2025.10.13.682078

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