It is widely accepted that interleukin-1␤ (IL-1␤), a cytokine produced not only by immune cells but also by glial cells and certain neurons inf luences brain functions during infectious and inf lammatory 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-1␤ gene expression is substantially increased during longterm 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-1␤ 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.Interleukin-1␤ (IL-1␤), which is assigned a key role in the orchestration of the complex immune response to infection and injury (1), was originally described as an immune cell mediator in the periphery. More recently, however, this cytokine has been reported to be synthesized also in the brain by glial cells and certain neurons; and IL-1 receptors were found in different regions of the CNS with the highest abundance in the hippocampus (for review see refs. 2-4). These complementary findings indicate a physiological role of IL-1 in the brain. In support of this, pharmacological and behavioral studies demonstrated the capacity of IL-1␤ to affect various neuroendocrine functions, to alter the release and turnover rate of certain neurotransmitters and modulators [e.g., norepinephrine, dopamine, gamma-aminobutyric acid (GABA), nitric oxide (NO), corticotropin-releasing hormone (CRH), refs. 5-11], and to induce changes in behavior (12-14). However, in most of these studies relatively high doses of IL-1␤ were applied or the data were obtained during pathological conditions in which a massive IL-1␤ production in the CNS occurs. Furthermore, there is as yet no experimental evidence of whether the expression of IL-1␤ gene is affected by physiological changes in the activity of discrete populations of brain neurons and whether such changes have implications for brain functions. We approached these questions by using long-term potentiation (LTP), a well-established cellular model of synaptic plasticity (15)(16)(17). The hallmark of LTP is a sustained enhancement of synaptic transmission and postsynaptic neuronal activity after high frequency stimulation of afferent fibers. Here,...

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.

Whole-cell currents from >70 voltage-clamped bipolar cells were recorded in a slice preparation of the rat retina. The recorded cells were identified and classified by intracellular staining with Lucifer yellow. Glutamate, the specific agonists (+/-)-2-amino-4-phosphonobutyric acid (AP-4) and kainate (KA), and the antagonist 6-cyanoquinoxaline-2,3-dione (CNQX) were applied. The cells could be isolated from presynaptic influences by the co-application of bicuculline, strychnine, and cobalt ions. Responses to AP-4 were elicited only from bipolar cells with axons stratifying in the inner part of the inner plexiform layer (IPL). AP-4 caused an outward current in these cells attributable to the closure of nonspecific cation channels. Responses to kainate representing a direct action of the drug on the recorded cells were observed only in bipolar cells with axons stratifying in the outer part of the IPL. KA caused a CNQX-sensitive inward current in these cells, associated with openings of nonspecific cation channels. The results predict that cone bipolar (CB) cells with axons terminating in the outer IPL are OFF-bipolars, whereas those with axons terminating in the inner IPL are ON-bipolars. Most of the cells expressed GABA-gated Cl- conductances. In rod bipolar and in some CB cells, only part of the GABA-induced currents could be blocked by the application of bicuculline, suggesting the presence of GABAc receptors in addition to GABAA receptors.

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.