Non-canonical Mechanisms of Presynaptic Kainate Receptors Controlling Glutamate Release

Negrete-Díaz, José Vicente; Sihra, Talvinder S.; Flores, Gonzalo; Rodríguez‐Moreno, Antonio

doi:10.3389/fnmol.2018.00128

Cited by 32 publications

(26 citation statements)

References 83 publications

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“…Kainate-type glutamate receptors are well-established mediators of canonical, ionotropic postsynaptic transmission and, presynaptically, these receptors support a modulatory regulation of neurotransmitter release. In the latter regard, kainate receptors (KARs) have a non-canonical metabotropic capacity, through which they effect the control of both glutamate and GABA release (for review see [1,2,3,4,5,6,7,8,9]). At several excitatory glutamatergic synapses, the KAR-mediated modulation is found to be biphasic, such that low agonist concentrations facilitate glutamate release, as opposed to higher agonist concentrations, which inhibit neurotransmitter release (see [2,3,4,5,9,10] for reviews).…”

Section: Introductionmentioning

confidence: 99%

Kainate Receptor-Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum

Falcón-Moya

Losada-Ruiz

Rodríguez‐Moreno

2019

IJMS

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Kainate (KA) receptors (KAR) have important modulatory roles of synaptic transmission. In the cerebellum, the action mechanisms of KAR-mediated glutamatergic depression are unknown. We studied these mechanisms by recording evoked excitatory postsynaptic currents (eEPSCs) from cerebellar slices using the whole-cell configuration of the patch-clamp technique. We observed that 3 μM KA decreased the amplitude of eEPSCs and increased the number of failures at the synapses established between parallel fibers (PF) and Purkinje neurons, and the effect was antagonized by NBQX under the condition where AMPA receptors were previously blocked. The inhibition of protein kinase A (PKA) suppressed the effect of KAR activation on eEPSC, and effect was not prevented by protein kinase C inhibitors. Furthermore, in the presence of Pertussis toxin, the depression of glutamate release mediated by KAR activation was prevented, invoking the participation of a Gi/o protein in this modulation. Finally, the KAR-mediated depression of glutamate release was not prevented by blocking calcium-permeable KARs or by treatments that affect calcium release from intracellular stores. We conclude that KARs present at these synapses mediate an inhibition of glutamate release through a mechanism that involves the activation of G-protein and protein kinase A.

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Section: Introductionmentioning

confidence: 99%

Kainate Receptor-Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum

Falcón-Moya

Losada-Ruiz

Rodríguez‐Moreno

2019

IJMS

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“…During repetitive stimulation Kainate autoreceptors in MF terminals facilitate Ca 2+ influx (Kamiya et al, 2002;Lauri et al, 2003;Scott et al, 2008;Andrade-Talavera et al, 2012). The rise in intracellular Ca 2+ is linked to the aforementioned increase in cAMP by Ca (Lauri et al, 2001b;Andrade-Talavera et al, 2012;Negrete-Díaz et al, 2018). In this way, these receptors participate in short-and long-term plasticity in MF terminals (Lauri et al, 2001a(Lauri et al, , 2001bSchmitz et al, 2001;Ji and Stäubli, 2002;Contractor et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of KARs in the mossy fibers has been shown to have a wide range of effects from facilitating synaptic responses under small concentrations of kainate (Lauri et al, 2001a;Schmitz et al, 2001;Ji and Stäubli, 2002) to depressing synaptic responses when applying higher kainate concentrations (Kamiya and Ozawa, 2000;Schmitz et al, 2000). On the other hand, in SC, activation of KAR only leads to synaptic depression (Chittajallu et al, 1996;Frerking et al, 2001;Negrete-Díaz et al, 2018). Since KARs do not trigger facilitation in SC, the absence of Mover does not affect it in this synapse.…”

Section: Discussionmentioning

confidence: 99%

Increased synaptic facilitation and exploratory behavior in mice lacking the presynaptic protein Mover

Viotti

et al. 2019

Preprint

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The enormous increase in the complexity of brains during evolution is accompanied by a remarkably small number of new, vertebrate-specific presynaptic proteins. These proteins are unlikely to be essential for transmitter release, because invertebrate synapses do not need them.But what functions do they fulfill? We show that the vertebrate-specific protein Mover is involved in constraining the release of neurotransmitters in some synapses in the hippocampus, while not affecting others. We further demonstrate that the absence of this protein leads to decreased anxiety levels. Understanding the function of such a protein can help us further understand synaptic transmission, the specializations that are brought about in vertebrate synapses, and how this can help or hinder neurological or psychiatric disorders. AbstractIn vertebrates and invertebrates, neurotransmitter release relies on a highly conserved molecular machinery. A surprisingly small number of presynaptic proteins evolved specifically in vertebrates. How they expand the power or versatility of the conserved core machinery is unclear.One of these vertebrate-specific proteins, called Mover / TPRGL / SVAP30, is heterogeneously expressed throughout the brain, suggesting that it adds special functions to subtypes of presynaptic terminals. In this study we generated Mover knockout mice to investigate the role of Mover from synaptic transmission to behavior. Deletion of Mover did not affect synaptic transmission at CA3 to CA1 synapses. In contrast, Mover deficient mice had strongly increased short-term facilitation at mossy fiber to CA3 synapses. This increase included frequency facilitation, a hallmark of mossy fiber terminal function. The effect was age-and Ca 2+ -dependent, and relied on the Kainate receptor/cAMP pathway in the mossy fiber terminals. Despite this change in presynaptic plasticity, the absence of Mover did not affect long-term spatial reference memory or working memory, but led to reduced anxiety. These discoveries suggest that Mover has distinct roles at different synapses. At mossy-fiber terminals, it acts to constrain the extent of presynaptic facilitation. Its role in activity-dependent neurotransmission could be necessary for normal anxiety responses.

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“…Kainate receptors display different modes of signaling and a metabotropic action of kainate receptors has been involved in presynaptic regulation and inhibition of GABA release [42,43]. A preferential expression of kainate receptors on inhibitory spinal neurons might therefore be involved in a glutamate-mediated inhibition of GABA (and glycine?)…”

Section: Differential Use Of Neurotransmitter Signaling Pathwaysmentioning

confidence: 99%

Neuron Type-Specific Translatomes in Spinal Cords of Naïve and Neuropathic Mice

Gupta

Scheurer

Pelczar

et al. 2020

Preprint

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The spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, the molecular identity of the underlying neurons and signaling mechanisms are still only partially understood. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (VGLUT2 + ) and inhibitory GABA and/or glycinergic (VGAT + or Gad67 + ) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are primarily set apart by the expression of genes encoding transcription factors or genes related to the production, release or re-uptake of their principal neurotransmitters (glutamate, GABA or glycine). Subsequent gene ontology (GO) term analyses revealed that neuropeptide signaling-related GO terms were highly enriched in the excitatory population. Eleven neuropeptide genes displayed largely non-overlapping expression patterns closely adhering to the laminar and hence also functional organization of the spinal cord grey matter, suggesting that they may serve as major determinants of modality-specific processing. Since this modality-specific processing of sensory input is severely compromised in chronic, especially neuropathic, pain, we also investigated whether peripheral nerve damage changes the neuron typespecific translatome. In summary, our results suggest that neuropeptides contribute to modalityspecific sensory processing in the spinal cord but also indicate that altered sensory encoding in neuropathic pain states occurs independent of major translatome changes in the spinal neurons.The ability to sense and discriminate different noxious and innocuous somatosensory stimuli is essential for all higher animals and humans in order to react adequately to external stimuli and internal conditions [1,2]. The spinal dorsal horn, i.e., the sensory part of the spinal cord, constitutes a key element in this process. It receives somatosensory signals from peripheral neurons and processes these signals together with other inputs descending from supraspinal sites in a complex network of inhibitory and excitatory interneurons before relaying these signals via projection neurons to supraspinal centers [3]. Projection neurons make up less than 10% of all dorsal horn neurons, while more than 90% of the neuronal population are interneurons of which, between 60 and 70% are excitatory glutamatergic neurons, and the rest is inhibitory (GABA and/or glycinergic).The spinal cord is organized in a laminar fashion, which has initially been proposed on the basis of differences in cell density and morphology between the different laminae [4, 5] but has later been shown to also reflect functional organization. This is especially reflected for example by the lamina specific innervation pattern by ...

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Non-canonical Mechanisms of Presynaptic Kainate Receptors Controlling Glutamate Release

Cited by 32 publications

References 83 publications

Kainate Receptor-Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum

Kainate Receptor-Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum

Increased synaptic facilitation and exploratory behavior in mice lacking the presynaptic protein Mover

Neuron Type-Specific Translatomes in Spinal Cords of Naïve and Neuropathic Mice

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