The Regulations and Role of Cytokines in Models of Synaptic Activity and Plasticity

While many functions have been proposed for cytokines in the CNS, most research has focused on injury and infection. Initially described as protein signaling molecules between cells of the immune system, many cytokines and their receptors have since been localized to both the central and peripheral nervous systems. Our experiments explore the contribution of cytokines to the fundamental brain functions, neuronal activity and synaptic plasticity. Since cytokines are up-regulated by brain trauma, we first asked if cytokine mRNA expression is affected by the procedures used to make hippocampal slices and to study long term potentiation (LTP) in vivo. Indeed, expression of many cytokines is altered in the preparation of hippocampal slices, and we find even more dramatic cytokine changes with electrode penetration in vivo. We therefore turned to a chronic in vivo preparation in which the effects of injury are eliminated by a three week recovery period between electrode placement and electrophysiological stimulation. In this preparation, we find that brain derived neurotrophic factor expression is decreased by low-frequency test stimuli. More dramatically, interleukin-6 (IL-6) is up-regulated specifically by LTP induction. Since IL-6 can regulate neuronal activity, this finding suggests a role for IL-6 in the control of LTP. We also studied the regulation of neuropoietic cytokines by neuronal activity in the hippocampus using pilocarpine-induced seizure. Using a semi-quantitative RNase protection assay, we find that leukemia inhibitory factor (LIF) and oncostatin M are strongly up-regulated by seizure activity. Each cytokine is, however, induced in discrete cell populations with a distinct time course, suggesting particular roles in both the seizure and in its pathological consequences. The relatively rapid induction of LIF in hippocampal astrocytes suggested that this cytokine could control astrocyte activation in response to seizure. Using the electroconvulsive shock (ECS) model of seizure in LIF knockout and wild type mice, and glial fibrillary acidic protein (GFAP) induction as the marker of astrocyte activation, we find that LIF is required for GFAP up-regulation. In sum, certain cytokines are regulated by particular patterns of neuronal activity, including those thought to be involved in learning and memory. Moreover, one cytokine, LIF, is required for astrocytic activation, a key process in subsequent hippocampal pathology.