•Increased CNS expression of CCL2 reduced alcohol consumption.•Both dependent and non-dependent mice showed altered behavior.•Increased CNS expression of CCL2 altered effects of alcohol on spatial learning.•Increased CNS expression of CCL2 altered effects of alcohol on associative learning.Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine ligand 2 (CCL2). The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated. Our studies focus on the hypothesis that increased levels of CCL2 in the CNS produce neuroadaptive changes that modify the actions of alcohol on the CNS. We utilized behavioral testing in transgenic mice that express elevated levels of CCL2 to test this hypothesis. The increased level of CCL2 in the transgenic mice involves increased astrocyte expression. Transgenic mice and their non-transgenic littermate controls were subjected to one of two alcohol exposure paradigms, a two-bottle choice alcohol drinking procedure that does not produce alcohol dependence or a chronic intermittent alcohol procedure that produces alcohol dependence. Several behavioral tests were carried out including the Barnes maze, Y-maze, cued and contextual conditioned fear test, light–dark transfer, and forced swim test. Comparisons between alcohol naïve, non-dependent, and alcohol-dependent CCL2 transgenic and non-transgenic mice show that elevated levels of CCL2 in the CNS interact with alcohol in tests for alcohol drinking, spatial learning, and associative learning.

•Elevated CNS expression of IL-6 increases the late form of LTP in the hippocampus.•Rapamycin, an antagonist of mTOR, reduced genotypic differences in L-LTP.•Rapamycin reduced synaptic responses during LTP induction in IL-6-tg hippocampus.The neuroimmune factor IL-6 has been shown to regulate hippocampal long-term potentiation (LTP), an activity-dependent enhancement of synaptic transmission that plays a central role in memory and learning. This IL-6 action was demonstrated with relatively short IL-6 exposure, and may reflect physiological actions of IL-6. IL-6 is also expressed chronically at elevated levels in the central nervous system (CNS) under pathological conditions such as neurological disorders. Little is known about the effects IL-6 on LTP under such conditions, an issue that we are addressing by electrophysiological recordings from CA1 pyramidal neurons of hippocampal slices from transgenic mice that persistently express elevated levels of IL-6 in the CNS (IL-6 tg). The current studies examined the long-lasting phase of LTP (late LTP; L-LTP) and the potential involvement mammalian target of rapamycin (mTOR), a known regulator of L-LTP and a downstream partner of IL-6 signal transduction pathways. Results show that basal synaptic transmission and L-LTP were increased in hippocampal slices from IL-6 tg mice compared to slices from non-transgenic (non-tg) control mice. An inhibitor of mTOR, rapamycin, reduced L-LTP in slices from both genotypes, and eliminated the difference in magnitude of L-LTP between IL-6 and non-tg hippocampus. There were no genotypic effect of rapamycin on basal synaptic transmission, but synaptic responses during the LTP induction protocol were reduced in IL-6 tg slices, an effect that could contribute to the reduction of L-LTP in the IL-6 tg slices. These results indicate that persistently increased levels of IL-6 can lead to alterations in mTOR regulation of L-LTP, possibly affecting learning and memory.

Recent studies have established the existence of an innate immune system in the central nervous system (CNS) and implicated a critical role for this system in both normal and pathological processes. Astrocytes and microglia, normal components of the CNS, are the primary cell types that comprise the innate immune system of the CNS. Basic to their role during normal and adverse conditions is the production of neuroimmune factors such as cytokines and chemokines, which are signaling molecules that initiate or coordinate downstream cellular actions. During adverse conditions, cytokines and chemokines function in defensive and repair. However, if expression of these factors becomes dysregulated, abnormal CNS function can result. Both neurons and glial cells of the CNS express receptors for cytokines and chemokines, but the biological consequence of receptor activation has yet to be fully resolved. Our studies show that neuroadaptive changes are produced in primary cultures of rat cerebellar cells chronically treated with the cytokine interleukin-6 (IL-6) and in the cerebellum of transgenic mice that chronically express elevated levels of IL-6 in the CNS. In the cerebellum in culture and in vivo, the neuroadaptive changes included alterations in the level of expression of proteins involved in gene expression, signal transduction, and synaptic transmission. Associated with these changes were alterations in neuronal function. A comparison of results from the cultured cerebellar cells and cerebellum of the transgenic mice indicated that the effects of IL-6 can vary across neuronal types. However, alterations in mechanisms involved in Ca2+ homeostasis were observed in all cell types studied. These results indicate that modifications in cerebellar function are likely to occur in disorders associated with elevated levels of IL-6 in the cerebellum.

Tight regulation of calcium (Ca2+) dynamics is critical for all neurons. Ca2+ is a major mediator of cellular excitability, synaptic plasticity, and regulation of transcription, amongst others. Recent years have seen major developments in terms of understanding the roles of Ca2+ signals in the cerebellar circuitry, especially for Purkinje neurons and granule cells. The unique morphology of Purkinje neurons serves as a platform to unravel the secrets of Ca2+ homeostasis in cerebellar microcircuits. This special issue covers recent advances in Ca2+ signaling and imaging, and highlights the importance of spatiotemporal compartmentalization underlying Ca2+ dynamics. Sorting out the pieces of the puzzle of homeostatic regulation of Ca2+ remains an instrumental step to start rational therapies of Ca2+ deregulation.

•IL-6 is an important neuroimmune factor that is produced by CNS neurons and glial.•Elevated levels of IL-6 occur in the CNS in association with impair cognitive function.•IL-6 regulates CNS neuronal and synaptic function through a variety of mechanisms.•Prolonged exposure to IL-6 can result in persistent neuroadaptive changes that alter CNS function.A growing body of evidence supports a role for glial-produced neuroimmune factors, including the cytokine IL-6, in CNS physiology and pathology. CNS expression of IL-6 has been documented in the normal CNS at low levels and at elevated levels in several neurodegenerative or psychiatric disease states as well as in CNS infection and injury. The altered CNS function associated with these conditions raises the possibility that IL-6 has neuronal or synaptic actions. Studies in in vitro and in vivo models confirmed this possibility and showed that IL-6 can regulate a number of important neuronal and synaptic functions including synaptic transmission and synaptic plasticity, an important cellular mechanism of memory and learning. Behavioral studies in animal models provided further evidence of an important role for IL-6 as a regulator of CNS pathways that are critical to cognitive function. This review summarizes studies that have lead to our current state of knowledge. In spite of the progress that has been made, there is a need for a greater understanding of the physiological and pathophysiological actions of IL-6 in the CNS, the mechanisms underlying these actions, conditions that induce production of IL-6 in the CNS and therapeutic strategies that could ameliorate or promote IL-6 actions.This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’.

Signal transduction pathways may be important targets of chemokines during neuroinflammation. In the current study, Western blot analyses show that in rat hippocampal neuronal/glial cell cultures chronic CXCL10 increases the level of protein for ERK1/2 as well as for the transcriptional factors CREB and NF-κB. Bcl-2, an anti-apoptotic protein whose expression can be regulated by a pathway involving ERK1/2, CREB and NF-κB, was also increased in the CXCL10 treated cultures. These results implicate a role for ERK1/2, CREB and NF-κB in effects of CXCL10 on hippocampal cells and suggest that chronic CXCL10 may have a protective role during certain neuroinflammatory conditions.

•Effects of ethanol are altered in mice with increased astrocyte expression of IL-6.•Ethanol depression of the fEPSP and PS is not observed in IL-6 tg hippocampus.•Long-term synaptic plasticity is resistant to ethanol in the IL-6 tg hippocampus.•EEG activity during ethanol withdrawal is enhanced in IL-6 transgenic mice.A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including persistent changes in CNS function that contribute to cognitive dysfunction and the development of alcohol dependence.

IL-6 is an important signaling molecule in the CNS. CNS neurons express IL-6 receptors and their signal transduction molecules, consistent with a role for IL-6 in neuronal physiology. Research indicates that IL-6 levels are low in the normal brain but can be significantly elevated in CNS injury and disease. Relatively little is known about how the elevated levels of IL-6 affect neurons. In the current study we show that under conditions of chronic exposure, IL-6 induces alterations in the level of protein expression in developing CNS cells. Such changes may play a role in the altered CNS function observed in CNS conditions associated with elevated levels of IL-6 in the CNS.

We examined the effect of chronic CCL3 treatment on the properties of cultured rat hippocampal neurons to gain an understanding of the neuronal effects of CCL3 during neuroinflammatory disorders. Western blot assays showed that chronic exposure to CCL3 altered the level of specific neuronal and glial proteins and that CCL3 had no effect on neuronal survival. CCL3 treatment also altered intracellular Ca2+ dynamics and increased Ca2+ levels in hippocampal neurons, measured by fura-2 imaging techniques. Additionally, chronic CCL3 increased NMDA-evoked Ca2+ signals in the hippocampal neurons and increased NMDA receptor levels. These CCL3-induced neuroadaptive changes could play an important role in the CNS dysfunction associated with CNS disorders with a neuroinflammatory component.