Anti-hypoxic effect of interleukin-10 in hippocampal neurons is mediated by modulation of TASK-1 and TASK-3 channels activity.

It has been shown that anti-inflammatory cytokine interleukin-10 (IL-10) can exert anti-hypoxic effect preventing post-hypoxic neuronal hyperexcitability. Yet, exact mechanisms of IL-10 mediated anti-hypoxic action on neuronal function are not fully understood. We suggested that IL-10 can exert its anti-hypoxic action via modulation of activity of two-pore potassium TASK-1 and TASK-3 channels. To study the involvement of TASK-1 and TASK-3 channels we employed a combination of whole-cell patch clamp and pharmacological inhibitory analysis to assess if IL-10 and brief hypoxic episode can modulate K+ background leak current (Ileak) and membrane input resistance (Rin) in cultured hippocampal neurons. We found that IL-10 in a dose-dependent manner can significantly increase Ileak with concomitant reduction in Rin. Neurons that were exposed to brief hypoxic episode on contrary showed significant decrease in Ileak with concomitant increase in Rin. Pretreatment with IL-10 prior hypoxic episode was able to abolish negative effect of hypoxia on Ileak and Rin. IL-10 potentiating action on Ileak and Rin was occluded by co-addition of selective blockers of TASK-1 and TASK-3 channels - ML365 and PK-THPP. Co-addition of LY294002, an inhibitor of PI3-kinase occluded IL-10 action on Ileak and Rin showing involvement of PI3K-associated pathway in IL-10 mediated regulation of TASK channel function. Our results provide new insights into IL-10 mediated neuroprotective and anti-hypoxic actions showing TASK-1 and TASK-3 channels as downstream targets of this anti-inflammatory cytokine.

Interleukin-10 and transforming growth factor-ß1 facilitate long-term potentiation in CA1 region of hippocampus.

It has been shown that pro-inflammatory cytokines preferentially attenuate long-term potentiation (LTP), at the same time the effect of anti-inflammatory cytokines on synaptic plasticity has not been fully studied yet. Here we studied the effect of two anti-inflammatory cytokines - interleukin-10 (IL-10) and transforming growth factor-ß1 (TGF-ß1) on long-term potentiation. It was found that exogenously added IL-10 as well as TGF-ß1 were able to effectively facilitate LTP evoked with ether high frequency or theta burst stimulation protocols in CA1 area of hippocampus. Effectiveness of IL-10 and TGF-ß1 on LTP varied depending on the concentration of used cytokine and type of tetanic stimulation protocol used for LTP induction. Overall the positive effect of studied cytokines on LTP was associated with their ability to increase basal synaptic strength at Schaffer collateral - CA1 synapse. At the same time IL-10 and TGF-ß1 did not have any effect on short-term plasticity. Our results provide new evidence upon the modulatory effects that anti-inflammatory cytokines exert on synaptic plasticity further highlighting their potency as modulators of neuronal function.

Interleukin-10 Facilitates Glutamatergic Synaptic Transmission and Homeostatic Plasticity in Cultured Hippocampal Neurons.

Anti-inflammatory cytokines are known to exert neuroprotective action ameliorating aberrant neuronal network activity associated with inflammatory responses. Yet, it is still not fully understood if anti-inflammatory cytokines play a significant role in the regulation of synaptic activity under normal conditions. Thus, the aim of our study was to investigate the effect of Interleukin-10 (IL-10) on neuronal synaptic transmission and plasticity. For this we tested the effect of IL-10 on miniature excitatory postsynaptic currents (mEPSC) and intracellular Ca2+ responses using whole-cell patch clamp and fluorescence microscopy in 13-15 DIV primary hippocampal neuroglial culture. We found that IL-10 significantly potentiated basal glutamatergic excitatory synaptic transmission within 15 min after application. Obtained results revealed a presynaptic nature of the effect, as IL-10 in a dose-dependent manner significantly increased the frequency but not the amplitude of mEPSC. Further, we tested the effect of IL-10 on mEPSC in a model of homeostatic synaptic plasticity (HSP) induced by treatment of primary hippocampal culture with 1 µM of tetrodotoxin (TTX) for a 24 h. It was found that 15 min application of IL-10 at established HSP resulted in enhanced mEPSC frequency, thus partially compensating for a decrease in the mEPSC frequency associated with TTX-induced HSP. Next, we studied if IL-10 can influence induction of HSP. We found that co-incubation of IL-10 with 1 µM of TTX for 24 h induced synaptic scaling, significantly increasing the amplitude of mEPSC and Ca2+ responses to application of the AMPA agonist, 5-Fluorowillardiine, thus facilitating a compensatory postsynaptic mechanism at HSP condition. Our results indicate that IL-10 potentiates synaptic activity in a dose- and time-dependent manner exerting both presynaptic (short-term exposure) and postsynaptic (long-term exposure) action. Obtained results demonstrate involvement of IL-10 in the regulation of basal glutamatergic synaptic transmission and plasticity at normal conditions.

Changes in the level of fatty acids in the brain of rats during memory acquisition.

Memory acquisition is accompanied by many cellular and molecular processes, and it is not always clear what role they play. Fatty acids (FAs) are known to be important for cognitive functions, but the details of their involvement in memory processes remain unknown. We investigated FAs in the prefrontal cortex and hippocampus of rats trained to perform a task with food reinforcement. The learning consisted of two training sessions, each of which included 10 trials. The results showed that such training altered individual FAs in the brains. The most significant changes were in the prefrontal cortex, where an increase in the level of many FAs occurred, especially after the second training session: palmitic (16:0), stearic (18:0), docosahexaenoic (22:6, n-3), arachidonic (22:4, n-6), docosapentaenoic (22:5, n-6) acids. Changes in the fatty acid level after training in rats were detected only in the left hippocampus, where the levels of palmitic, docosapentaenoic, and docosahexaenoic acids changed. The changes in the right hippocampus were not significant. In both the prefrontal cortex and the left hippocampus, 72 h after training, all FAs returned to control levels. We believe that the main role of a reversible increase in FA levels during memory acquisition is to support and protect cellular processes involved in memory acquisition. Consolidation of memory traces, which occurs mainly in the neocortex, requires protection from external influences, to which FAs makes a significant contribution. They are able to improve neuronal plasticity, enhance local blood flow, improve mitochondrial processes, and suppress pro-inflammatory signals.

Why Do Levels Of Anti-inflammatory Cytokines Increase During Memory Acquisition?

The role of anti-inflammatory cytokines in the mechanisms of learning and memory, modulation of synaptic plasticity in the mammalian brain has not received sufficient attention. These issues are discussed in this review, and among the many cytokines, attention is paid to the most studied in this respect IL-10, IL-4, IL-13 and TGF-ß. The level of anti-inflammatory cytokines in the brain tends to increase during memory acquisition, but the significance of such an increase is unclear. We hypothesize that anti-inflammatory cytokines primarily protect and optimize the functioning of neuronal circuits involved in information processing. The increased local activity of neurons during memory acquisition activates many signaling molecules, and some of them can trigger unwanted processes (including neuroinflammation), but increased levels of anti-inflammatory cytokines prevent this triggering. Each of the anti-inflammatory cytokines plays a specific role in supporting information processing. For example, the role of IL-4 and IL-13 in recruiting T cells to the meninges during training in healthy animals has been most studied. It has also been shown that TGF-ß is able to optimize late stage LTP in the hippocampus and support the consolidation of memory traces in behavioral studies. Cytokines have an effect on learning and memory through their influence on neuroplasticity, neurogenesis in the hippocampus and regulation of the neurovascular unit. Experiments have shown such an effect, and the data obtained create the prerequisites for new therapeutic approaches to the correction of cognitive impairments.

The role of anti-inflammatory cytokines in memory processing in a healthy brain.

The purpose of the work was to study the role of anti-inflammatory cytokines in memory processing in a healthy brain. Wistar rats were trained to perform a task with positive (food) reinforcement; and then the task performance was tested after intraventricular injection of IL-10 or TGF-ß1. A microinjection into the brain of either of the two cytokines did not affect the performance of the task and did not have an anti-amnesic effect when the retrieval was deteriorated with scopolamine. In addition, endogenous levels of IL-10 and TGF-ß1 were determine in the prefrontal cortex and in the hippocampus after one and two training sessions, consisting of 10 runs each. The level of IL-10 did not change after training both in the prefrontal cortex and in the hippocampus. Endogenous level of TGF-ß1 increased in the neocortex after the first training session, the second session, and recovered to the normal level three days after training. In contrast, in the hippocampus, the level of TGF-ß1 was decreased: maximally after the first training session in the right hippocampus and after the second training session in the left one. Given the role of the prefrontal cortex in memory processing, we assume that a specific increase of TGF-ß1 in the prefrontal cortex may indicate involvement in memory trace consolidation.

Deficiency of transforming growth factor-ß signaling disrupts memory processes in rats.

Cytokines, in addition to their participation in immune and inflammatory processes, play an important role in synaptic plasticity, neoneurogenesis, and cognitive functions. In our work, we aimed to clarify the role of the transforming growth factor-ß (TGF-ß), which is recognized as a multifunctional cytokine, in memory processes. Behavioral experiments were carried out in rats using step-through passive avoidance test. The results obtained showed that the learning of animals after treatment with SB431542, a selective inhibitor of TGF-ß receptors, was impaired, which indicated a significant memory deterioration. Nevertheless, the memory of rats remained at the control level when TGF-ß and SB431542 were coadministered. Thus, the role of TGF-ß in memory retrieval after the passive avoidance test was revealed: memory in rats was weakened if the TGF-ß signaling pathway was inhibited during learning. Evidently, successful consolidation of at least some types of memory requires a normal level of TGF-ß, indicating the modulation of cognitive functions by cytokines under normal physiological conditions.