Cytokines mediate glial - neuronal crosstalk - effects of IL-1ß on synaptic transmission

Schmerz ist eine lebenserhaltende biologische Funktion des Organismus, die den Körper sowohl vor potentiell gefährdenden, als auch vor bereits bestehenden Gewebeschäden warnt. Schmerz wird über die Aktivierung von Schmerzrezeptoren, sogenannten Nozizeptoren ausgelöst. Nozizeptoren sind spezialisierte Nervenendigungen, die auf starke mechanische, chemische und physikalische Reize reagieren. Die nozizeptive Information wird dann über schwach myelinisierte Aδ- und nicht myelinisierte C-Fasern in das Hinterhorn des Rückenmarks und in weiterer Folge in das Gehirn weitergeleitet, wo der Schmerz erstmals wahrgenommen wird. In den oberflächlichen Laminae I/II des Rückenmarks kann es an der ersten synaptischen Umschaltstelle zwischen afferenten Neuronen und verschiedenen nachgeschalteten Rückenmarksneuronen zur Modulation der nozizeptiven Information kommen. Unter pathologischen Bedingungen, wie peripheren Nervläsionen oder Entzündungen kann die nozizeptive Information moduliert werden. Hier kommt es zu einer veränderten Übertragung der nozizeptiven Information, die einer Verstärkung der Schmerzempfindlichkeit (Hyperalgesie) zugrunde liegen kann. Ein zelluläres Modell der Hyperalgesie ist die Langzeitpotenzierung (LTP) zwischen primär afferenten C-Fasern und nachgeschalteten Rückenmarksneuronen. Im Rückenmark nimmt sie eine Rolle als spinaler Schmerzverstärker ein, da es auf zellulärer Ebene zur längerfristigen Verstärkung der synaptischen Übertragung kommt. Im Zentrum der Beobachtungen standen zunächst lange Zeit neuronale Prozesse. Die Beteiligung nicht neuronaler Zellen an der synaptischen Plastizität wurde erst kürzlich untersucht. Neue Ergebnisse der letzten Jahre sprechen aber für die Bedeutung des am häufigst vorkommenden Zelltyps im zentralen Nervensystem: Gliazellen. Die Frage, die sich nun stellte, war, ob Gliazellen einen wesentlichen Einfluss auf die veränderte synaptische Übertragung bei einer spinalen LTP nehmen. 4 Transversalschnitte mit intakten dorsalen Wurzeln juveniler Ratten wurden angefertigt. Die dorsalen Wurzeln wurden mit einer Suction-Elektrode stimuliert und Ganzzellableitungen in Lamina I Neuronen des dorsalen Horns durchgeführt. Im Rahmen der Ganzzellableitungen wurden erregende postsynaptische Ströme (EPSCs) gemessen. Es wurde gezeigt, dass Gliazellen und das von Gliazellen sekretierte Zytokin IL-1ß die synaptische Übertragungsstärke beeinflussen können. Gliazellen scheinen, den aufkommenden Daten zufolge, eine wichtige Rolle in der synaptischen Plastizität zu spielen.Pain is described as an unpleasant sensory and emotional experience which protects the body from damaging or potentially damaging situations, by activation of nociceptors. Nociceptors react in response to noxious mechanical, chemical, and physical stimuli. The nociceptive information is then transmitted from primary afferent Aδ- or C-fibers to the spinal dorsal horn. Already at the first synapse, between nociceptors and spinal dorsal horn neurons, nociceptive information can be modulated. Under pathological conditions like peripheral nerve injury and inflammation, nociceptive information can be modulated, and may be associated with an increased pain perception (hyperalgesia). A cellular model of hyperalgesia is long-term potentiation (LTP) between primary afferents and nociceptive- projection neurons in spinal dorsal horn. Neuronal plasticity was long thought to be entirely controlled by neurons. Over the last years, glia have emerged as important contributors to pathological and chronic pain conditions. Question arises, whether glia cells crucially influence synaptic plasticity in pain pathways. Transversal spinal cord slices with dorsal roots attached were dissected from rats. Dorsal roots were stimulated and excitatory postsynaptic currents (EPSCs) were recorded in spinal dorsal horn neurons. We showed that glia cells responded to a conditioning stimulus which also induced potentiation of EPSC- amplitudes in spinal dorsal horn neurons. We further demonsrated that the cytokine IL-1ß, secreted by glia cells, can increase synaptic strength. These findings suggest involvement of IL-1ß in induction and maintenance of synaptic plasticity between primary afferents and spinal dorsal horn neurons. Taken together, glia cells seem to be potential modulators of nociceptive transmission, and therefore key contributors to the development of pathological and chronic pain

Physiological roles of Kv2 channels in entorhinal cortex layer II stellate cells revealed by Guangxitoxin-1E

The medial entorhinal cortex (mEC) is strongly involved in spatial navigation, memory, dementia and epilepsy. Although potassium channels shape neuronal activity, their roles in mEC are largely unknown. We used the new Kv2 blocker Guangxitoxin-1E (GTx; 10–100 nm) in rat brain slices to investigate Kv2 channel functions in mEC layer II stellate cells (SCs). These neurons project to the hippocampus and are considered to be grid cells representing space. Voltage clamp recordings from SCs nucleated patches showed that GTx inhibited a delayed rectifier K+ current activating beyond –30 mV but not transient A-type current. In current clamp, GTx (i) had almost no effect on the first action potential but markedly slowed repolarization of late spikes during repetitive firing; (ii) enhanced the after-depolarization (ADP); (iii) reduced fast and medium after-hyperpolarizations (AHPs); (iv) strongly enhanced burst firing and increased excitability at moderate spike rates but reduced spiking at high rates; and (v) reduced spike clustering and rebound potentials. The changes in bursting and excitability were related to the altered ADPs and AHPs. Kv2 channels strongly shape the activity of mEC SCs by affecting spike repolarization, after-potentials, excitability and spike patterns. GTx is a useful tool and may serve to further clarify Kv2 channel functions in neurons. We conclude that Kv2 channels in mEC SCs are important determinants of intrinsic properties that allow these neurons to produce spatial representation. The results of the present study may also be important for the accurate modelling of grid cells. This is the peer reviewed version of the article which has been published in final form at https://doi.org/10.1113/JP273024. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving

Kisspeptin modulates sexual and emotional brain processing in humans

BACKGROUND. Sex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior. METHODS. Using a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men. RESULTS. We demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood. CONCLUSIONS. Collectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function. FUNDING. National Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC)