Date of Award
Doctor of Philosophy (PhD)
James A. Hewett
Epilepsy, Hippocampus, Interleukin 1β, P2X7R, Seizure, Seizure threshold
The pro-inflammatory cytokine, Interleukin-1β (IL-1β), is well known for its ability to initiate and propagate inflammatory responses at sites of infection and tissue injury. Paradoxically at odds with this classic view, it is now clear that IL-1β signaling modulates a number of physiological functions in the central nervous system. In this regard, IL-1β is involved in sleep and body fluid regulation in the basal forebrain and hypothalamus, respectively, and plasticity changes that underlie cognition in the hippocampus. Evidence from a previous study in my laboratory further suggests that IL-1β regulates the innate seizure threshold, which arguably is a reflection of the homeostatic balance between excitation and inhibition (E/I) in the brain. Recognizing that the IL-1β signaling receptor, Interleukin 1 Receptor 1 (IL-1R1), is highly concentrated on granule neurons of the dentate gyrus of the hippocampal formation and that dysfunction of this brain region can shift the E/I balance toward excitation, my research focused on the possibility that constitutive IL-1β signaling in the hippocampal formation modulates brain E/I balance. The specific goal was to elucidate the cellular source(s) and release mechanism of IL-1β in the hippocampus and to examine the functional significance of this release in maintenance of the seizure threshold. In Aim 1, I used the PTZ acute seizure model and mice lacking IL-1R1 to confirm the previous results demonstrating that IL-1β signaling is required for maintenance of the innate seizure threshold. In Aim 2, using a brain-permeable antagonist of the ATP-activated purinergic receptor, P2RX7, I found that IL-1β immunoreactivity accumulated in pyramidal neurons of the CA3 and to a lesser extent in the CA1 subregions of the hippocampus. A subsequent study using hippocampal neuron cultures indicated P2RX7-dependent neuronal release of IL-1β and found that its subcellular localization included both cell bodies and processes of these neurons. Thirdly, I found that P2RX7 increased activity-dependent gene expression in cultures of hippocampal neurons and lowered the seizure threshold in a manner that resembled the phenotype of mice lacking IL-1R1 signaling. Together, results from this aim indicated strong possibility of basal IL-1β release from hippocampal neurons occurring via an ATP-dependent mechanism and contributing to maintaining the E/I balance of the normal brain. Additional results from studies in Aim 3 suggest that the rate of production and release of IL-1β is not affected by changes in neuronal excitation and that IL-1β may affect neuronal excitation via modulation of cyclooxygenase-2 function in hippocampus. Overall, the results from my dissertation research extend the knowledge of the biological function of IL-1β in the normal brain. A better understanding of this function could facilitate development of novel therapies to treat seizure induction in epileptic brains and perhaps reduce the probability of acquiring epilepsy in at-risk individuals.
Dutta, Spandita Seouli, "Neuromodulation by endogenous Interlukin-1β in hippocampus of the murine brain: Regulation of neuronal excitation" (2020). Dissertations - ALL. 1206.