GluK2 Q/R editing regulates kainate receptor signaling and long-term potentiation of AMPA receptors

Nair, Jithin D.; Wilkinson, Kevin A.; Yucel, Busra P.; Mulle, Christophe; Vissel, Bryce; Mellor, Jack; Henley, Jeremy M.

doi:10.1016/j.isci.2023.107708

Cited by 3 publications

(2 citation statements)

References 70 publications

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“…Genetic deletion of GluK5 does not impair this effect, whereas GluK2 is likely involved in both signaling modes [109,114,115]. A recent investigation showed that the GluK2 Q/R editing inhibits the metabotropic-like function in mouse CA3 postsynaptic KARs [116]. Therefore, edited and unedited GluK2 subunits could stimulate and inhibit glutamate release, respectively, the former probably in association with GluK5.…”

Section: Flux-independent Signaling By Presynaptic Kars Regulates Glu...mentioning

confidence: 98%

“…GluK5 cannot be targeted to the PM in the absence of GluK2 [8], which explains why KA fails to inhibit I sAHP and I mAHP in GluK2-deficient neurons. However, the GluK2 Q/R editing prevents the suppression of I sAHP induced by synaptic MF activation in CA3 pyramidal neurons [116]. Flux-independent signaling by KARs also regulates membrane excitability in CA3 interneurons.…”

Section: Flux-independent Signaling By Kars Regulates Axon Growth And...mentioning

confidence: 99%

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Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

Brunetti,

Soda,

Berra-Romani

et al. 2024

Biomedicines

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Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca2+ entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders.

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Section: Flux-independent Signaling By Presynaptic Kars Regulates Glu...mentioning

confidence: 98%

Section: Flux-independent Signaling By Kars Regulates Axon Growth And...mentioning

confidence: 99%

Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

Brunetti,

Soda,

Berra-Romani

et al. 2024

Biomedicines

View full text Add to dashboard Cite

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GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

Haikonen,

Szrinivasan,

Ojanen

et al. 2024

Mol Psychiatry

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Parvalbumin expressing interneurons (PV INs) are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV IN phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV INs in the lateral and basal amygdala (BLA). Ablation of GluK1 expression specifically from PV INs resulted in low parvalbumin expression and loss of characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV INs. Intriguingly, inactivation of GluK1 expression in adult PV INs was sufficient to abolish their high firing rate and to reduce PV expression levels, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed the balance between evoked excitatory vs. inhibitory synaptic inputs and long-term potentiation (LTP) in LA principal neurons, and resulted in aberrant development of the resting-state functional connectivity between mPFC and BLA. Behaviorally, the absence of GluK1 from PV INs associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV IN function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV IN malfunction.

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Overexpression of BDNF Suppresses the Epileptiform Activity in Cortical Neurons of Heterozygous Mice with a Transcription Factor Sip1 Deletion

Turovskaya,

Gavrish,

Tarabykin

et al. 2024

IJMS

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Since genetic mutations during brain development play a significant role in the genesis of epilepsy, and such genetically determined epilepsies are the most difficult to treat, there is a need to study the mechanisms of epilepsy development with deletions of various transcription factors. We utilized heterozygous mice (Sip1wt/fl) with a neuronal deletion of the transcription factor Sip1 (Smad interacting protein 1) in the cerebral cortex. These mice are characterized by cognitive impairment and are prone to epilepsy. It is known that the brain-derived neurotrophic factor (BDNF) has a neuroprotective effect in various neurodegenerative diseases. Therefore, we created and applied an adeno-associated construct carrying the BDNF sequence selectively in neurons. Using in vitro and in vivo research models, we were able to identify a key gen, the disruption of whose expression accompanies the deletion of Sip1 and contributes to hyperexcitation of neurons in the cerebral cortex. Overexpression of BDNF in cortical neurons eliminated epileptiform activity in neurons obtained from heterozygous Sip1 mice in a magnesium-free model of epileptiform activity (in vitro). Using PCR analysis, it was possible to identify correlations in the expression profile of genes encoding key proteins responsible for neurotransmission and neuronal survival. The effects of BDNF overexpression on the expression profiles of these genes were also revealed. Using BDNF overexpression in cortical neurons of heterozygous Sip1 mice, it was possible to achieve 100% survival in the pilocarpine model of epilepsy. At the level of gene expression in the cerebral cortex, patterns were established that may be involved in the protection of brain cells from epileptic seizures and the restoration of cognitive functions in mice with Sip1 deletion.

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GluK2 Q/R editing regulates kainate receptor signaling and long-term potentiation of AMPA receptors

Cited by 3 publications

References 70 publications

Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

Overexpression of BDNF Suppresses the Epileptiform Activity in Cortical Neurons of Heterozygous Mice with a Transcription Factor Sip1 Deletion

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