Presynaptic inhibition of segmental interneurons

In experiments on spinal cats changes in the second negative postsynaptic component (N₂) of the dorsal surface potential (DSP) of the spinal cord recorded in the region of segment L7 was used as the index of inhibition of segmental dorsal horn interneurons. Conditioning and testing stimuli were applied at increasing time intervals to the popliteal and superficial peroneal nerves respectively. Changes in the N₂ component were compared with changes in the N₁ component of the DSP, reflecting mainly activity of nonsegmental ascending dorsal horn interneurons. After an initial short facilitation a conditioning volley of pulses evokes prolonged (over 500 msec) inhibition of the N₂ component, characterized by the presence of two maxima (on the average at the 16th and 80th milliseconds) which indicate that two systems with different latent periods play a role in this inhibition. In its shape and temporal characteristics the curve of inhibition of the N₂ component corresponds to the two-component dorsal root potential (DRP) recorded in spinal animals in response to stimulation of flexor afferents (FRA) [8, 19]. Together with other features, this similarity is evidence of the presynaptic nature of this inhibition. Intravenous injection of hexobarbital has a stronger action on inhibition of the N₂ component, leading to a marked increase in its depth and duration. Suggestions are made regarding the functional organization of systems responsible for presynaptic inhibition of segmental dorsal horn interneurons.Deceased.Dnepropetrovsk State University. Translated from Neirofiziolgiya, Vol. 4, No. 1, pp. 75–82, January–February, 1972.     

Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response

While numerous small ubiquitin‐like modifier (SUMO) conjugated substrates have been identified, very little is known about the cellular signalling mechanisms that differentially regulate substrate sumoylation. Here, we show that acetylation of SUMO E2 conjugase Ubc9 selectively downregulates the sumoylation of substrates with negatively charged amino acid‐dependent sumoylation motif (NDSM) consisting of clustered acidic residues located downstream from the core ψ‐K‐X‐E/D consensus motif, such as CBP and Elk‐1, but not substrates with core ψ‐K‐X‐E/D motif alone or SUMO‐interacting motif. Ubc9 is acetylated at residue K65 and K65 acetylation attenuates Ubc9 binding to NDSM substrates, causing a reduction in NDSM substrate sumoylation. Furthermore, Ubc9 K65 acetylation can be downregulated by hypoxia via SIRT1, and is correlated with hypoxia‐elicited modulation of sumoylation and target gene expression of CBP and Elk‐1 and cell survival. Our data suggest that Ubc9 acetylation/deacetylation serves as a dynamic switch for NDSM substrate sumoylation and we report a previously undescribed SIRT1/Ubc9 regulatory axis in the modulation of protein sumoylation and the hypoxia response.     

Discriminating among complex signals: the roles of inhibition for creating response selectivities

The review deals largely with studies from my laboratory that were prompted by conversations I had with Gerhard Neuweiler more than 15 years ago. The studies were conducted on bats and dealt with mechanisms that enable the population of neurons in the inferior colliculus (IC) to respond selectively to the variety of signals bats emit for both communication and echolocation. The first section is concerned with how neurons in the dorsal nucleus of the lateral lemniscus (DNLL), the nucleus ventral to the IC, respond to species-specific signals and how they compare to responses of IC neurons evoked by the same signals. Those studies showed that DNLL neurons have no sideband inhibition and their responses are determined by excitation. In contrast, inhibition dominates in the IC where it carves out highly selective discharge properties. Those studies, in turn, raised questions about the quantitative features of inhibition that could only be answered with more sophisticated techniques. In the second section, results from analyses with spectrotemporal receptive fields (STRFs) are presented, and in the final section I show data derived from in vivo whole cell recordings that illustrate how features of inhibition interact with excitation to generate directionality selective responses in the IC.     

Presynaptic inhibition of nociceptive neurotransmission by somatosensory neuron-secreted suppressors

Noxious stimuli cause pain by activating cutaneous nociceptors.The Aδ-and C-fibers of dorsal root ganglion(DRG) neurons convey the nociceptive signals to the laminae Ⅰ—Ⅱ of spinal cord.In the dorsal horn of spinal cord,the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons,and by serotonin,norepinepherine and dopamine from the descending inhibitory system.In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord,the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited.In this review,we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons,the BNP/NPR-A/PKG/BK_(Ca) channel pathway,the FSTL1/α1Na~+-K~+ ATPase pathway and the activin C/ERK pathway.These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.     

Two distinct channels of olfactory bulb output

Rhythmic neural activity is a hallmark of brain function, used ubiquitously to structure neural information. In mammalian olfaction, repetitive sniffing sets the principal rhythm but little is known about its role in sensory coding. Here, we show that mitral and tufted cells, the two main classes of olfactory bulb projection neurons, tightly lock to this rhythm, but to opposing phases of the sniff cycle. This phase shift is established by local inhibition that selectively delays mitral cell activity. Furthermore, while tufted cell phase is unperturbed in response to purely excitatory odorants, mitral cell phase is advanced in a graded, stimulus-dependent manner. Thus, phase separation by inhibition forms the basis for two distinct channels of olfactory processing.     

Presynaptic modulation of sensory afferents in the invertebrate and vertebrate nervous system

• 1.1. Ultrastructural examination of the central terminals of sensory afferent neurons in both invertebrates and vertebrates demonstrates that the synapses that form the substrate for presynaptic inhibition and facilitation are almost universally present.
• 2.2. Presynaptic modulation of afferent input acts in many ways which tailor the inflow of sensory information to the behaviour of the animal, effectively providing a means of turning this on and off, or of combining information of the same or different modalities to refine responsiveness or clarify ambiguity.
• 3.3. Presynaptic modulation may act in several different roles on the same afferent.
• 4.4. A comparison of the mechanisms of presynaptic inhibition in different animals demonstrates the likelihood of a variety of common mechanisms,several of which may act simultaneously on the same terminal.These include changes in the conductance of the afferent membrane to Cl^-, K⁺and Ca²⁺ions, in addition to less well understood mechanisms that directly affect transmitter release.
• 5.5.A single transmitter can produce several effects on a terminal through the same or different receptors.
• 6.6. Ultrastructural studies of afferent terminals reveal that only a proportion of boutons on a given afferent may receive presynaptic input and that this may depend on the region of the nervous system in which these are found or on the identity of the postsynaptic neurons contacted.
• 7.7. The synaptic relationships of afferent terminals can be complex. In invertebrates different types of presynaptic neuron may interact synaptically,as may postsynaptic dendrites in vertebrates.
• 8.8. Axons presynaptic to afferent terminals in vertebrates frequently synapse also with dendrites postsynaptic to the afferents.
• 9.9. In both invertebrates and vertebrates reciprocal interactions between afferents and postsynaptic neurons are seen.
• 10.10. Ultrastructural immunocytochemistry reveals the likely dominance of GABA as an agent of presynaptic inhibition but also demonstrates the possible presence of other transmitters some of whose roles are less completely understood.

     

Presynaptic actions of endocannabinoids mediate alpha-MSH-induced inhibition of oxytocin cells

We recently showed that central injections of alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits oxytocin cells and reduces peripheral release of oxytocin, but induces oxytocin release from dendrites. Dendritic oxytocin release can be triggered by agents that mobilize intracellular calcium. Oxytocin, like alpha-MSH, mobilizes intracellular calcium stores in oxytocin cells and triggers presynaptic inhibition of afferent inputs that is mediated by cannabinoids. We hypothesized that this mechanism might underlie the inhibitory effects of alpha-MSH. To test this, we recorded extracellularly from identified oxytocin and vasopressin cells in the anesthetized rat supraoptic nucleus (SON). Retrodialysis of a CB1 cannabinoid receptor antagonist to the SON blocked the inhibitory effects of intracerebroventricular injections of alpha-MSH on the spontaneous activity of oxytocin cells. We then monitored synaptically mediated responses of SON cells to stimulation of the organum vasculosum of the lamina terminalis (OVLT); this evoked a mixed response comprising an inhibitory component mediated by GABA and an excitatory component mediated by glutamate, as identified by the effects of bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione applied to the SON by retrodialysis. Application of CB1 receptor agonists to the SON attenuated the excitatory effects of OVLT stimulation in both oxytocin and vasopressin cells, whereas alpha-MSH attenuated the responses of oxytocin cells only. Thus alpha-MSH can act as a "switch"; it triggers oxytocin release centrally, but at the same time through initiating endocannabinoid production in oxytocin cells inhibits their electrical activity and hence, peripheral secretion.     

The jamming avoidance response ofEigenmannia: properties of a diencephalic link between sensory processing and motor output

Summary Brain regions participating in the control ofEigenmannia's electric organ discharge frequency were localized by electrical microstimulation and anatomically identified by means of horseradish peroxidase deposition. A diencephalic region was found which, when stimulated, caused electric organ discharge (EOD) frequency increases of similar magnitude and time course as the frequency increases seen during the jamming avoidance response. Single unit recordings from this region revealed one cell type which preferentially responded to stimuli that cause the acceleration phase of the jamming avoidance response (electric organ discharge frequency increase). A second cell type responded preferentially to stimuli which cause EOD frequency decrease, and both cell types were tuned to stimuli which evoked maximal jamming avoidance behaviors.The results of the horseradish peroxidase experiments showed that the recording and stimulation sites correspond to the previously described nucleus electrosensorius. Our results confirm the earlier finding that this nucleus receives output from the torus semicircularis and we also found that the N. electrosensorius projects to the mesencephalic prepacemaker nucleus. The prepacemaker projects to the medullary pacemaker nucleus which generates the commands that evoke electric organ discharges.The anatomical and physiological results described here establish this diencephalic region as a link between the major sensory processing region for the jamming avoidance response, the torus semicircularis, and a mesencephalic pre-motor region, the prepacemaker nucleus.Abbreviations AM amplitude modulation - DF Delta F - ELLL electrosensory lateral line lobe - EOD electric organ discharge - JAR jamming avoidance response - NE nucleus electrosensorius - PPN prepacemaker nucleus - PN pacemaker nucleus     

PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects

The G protein-coupled, receptor-activated phosphoinositide 3-kinase gamma (PI3Kgamma) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration. Here, we report that mice carrying a targeted mutation in the PI3Kgamma gene causing loss of kinase activity (PI3KgammaKD/KD) display reduced inflammatory reactions but no alterations in cardiac contractility. We show that, in PI3KgammaKD/KD hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3KgammaKD/KD mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC). Finally, our data indicate that PI3Kgamma is an essential component of a complex controlling PDE3B phosphodiesterase-mediated cAMP destruction. Thus, cardiac PI3Kgamma participates in two distinct signaling pathways: a kinase-dependent activity that controls PKB/Akt as well as MAPK phosphorylation and contributes to TAC-induced cardiac remodeling, and a kinase-independent activity that relies on protein interactions to regulate PDE3B activity and negatively modulates cardiac contractility.     

Presynaptic inhibition of transmitter release from rat sympathetic neurons by bradykinin

Bradykinin is known to stimulate neurons in rat sympathetic ganglia and to enhance transmitter release from their axons by interfering with the autoinhibitory feedback, actions that involve protein kinase C. Here, bradykinin caused a transient increase in the release of previously incorporated [3H] noradrenaline from primary cultures of dissociated rat sympathetic neurons. When this effect was abolished by tetrodotoxin, bradykinin caused an inhibition of tritium overflow triggered by depolarizing K+ concentrations. This inhibition was additive to that caused by the alpha2-adrenergic agonist UK 14304, desensitized within 12 min, was insensitive to pertussis toxin, and was enhanced when protein kinase C was inactivated. The effect was half maximal at 4 nm and antagonized competitively by the B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor indomethacin and the angiotensin converting enzyme inhibitor captopril did not alter the inhibition by bradykinin. The M-type K+ channel opener retigabine attenuated the secretagogue action of bradykinin, but left its inhibitory action unaltered. In whole-cell patch-clamp recordings, bradykinin reduced voltage-activated Ca2+ currents in a pertussis toxin-insensitive manner, and this action was additive to the inhibition by UK 14304. These results demonstrate that bradykinin inhibits noradrenaline release from rat sympathetic neurons via presynaptic B2 receptors. This effect does not involve cyclooxygenase products, M-type K+ channels, or protein kinase C, but rather an inhibition of voltage-gated Ca2+ channels.     

Synchronized cluster firing,a distinct form of sensory neuron activation,drives spontaneous pain

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