H. Schneider

It is widely accepted that interleukin-1beta (IL-1beta), a cytokine produced not only by immune cells but also by glial cells and certain neurons influences brain functions during infectious and inflammatory processes. It is still unclear, however, whether IL-1 production is triggered under nonpathological conditions during activation of a discrete neuronal population and whether this production has functional implications. Here, we show in vivo and in vitro that IL-1beta gene expression is substantially increased during long-term potentiation of synaptic transmission, a process considered to underlie certain forms of learning and memory. The increase in gene expression was long lasting, specific to potentiation, and could be prevented by blockade of potentiation with the N-methyl-D-aspartate (NMDA) receptor antagonist, (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Furthermore, blockade of IL-1 receptors by the specific interleukin-1 receptor antagonist (IL-1ra) resulted in a reversible impairment of long-term potentiation maintenance without affecting its induction. These results show for the first time that the production of biologically significant amounts of IL-1beta in the brain can be induced by a sustained increase in the activity of a discrete population of neurons and suggest a physiological involvement of this cytokine in synaptic plasticity.

It is known that proinflammatory cytokines such as interleukin-6 (IL-6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL-6 in the "healthy" brain in synaptic plasticity and memory consolidation. During long-term potentiation (LTP) in vitro and in freely moving rats, IL-6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N-methyl-D-aspartate receptors with (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Blockade of endogenous IL-6 by application of a neutralizing anti-IL-6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL-6, 90 min after hippocampus-dependent spatial alternation learning resulted in a significant improvement of long-term memory. In view of the suggested role of LTP in memory formation, these data implicate IL-6 in the mechanisms controlling the kinetics and amount of information storage.

All-amacrine cells are crucial interneurons in the rod pathway of the mammalian retina. They receive input synapses from rod bipolar cells and make electrical output synapses into the ON-pathway and glycinergic chemical synapses into the OFF-pathway. Whole-cell currents from more than 50 voltage-clamped All-amacrine cells were recorded in a slice preparation of the rat retina. The recorded cells were identified by intracellular staining with Lucifer yellow. Spike-like potentials could be elicited upon depolarization by current injection. A voltage-activated, fast, TTX-sensitive, inward Na+ current was identified. A prominent outward K+ current could be suppressed by tetraethylammonium. GABA as well as glycine activated Cl- channels, which could be blocked by bicuculline and strychnine, respectively. Four agonists of excitatory amino acid receptors--kainate (KA), AMPA, 2-amino-4-phosphonobutyrate (APB), and NMDA--were tested. Inward currents at holding potentials of VH = -70 mV were found by application of KA and AMPA but not by application of APB and NMDA. These currents could be blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). ACh did not evoke any current responses.