Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Mahadevan, Vivek; Khademullah, C. Sahara; Dargaei, Zahra; Chevrier, Jonah; Uvarov, Pavel; Kwan, Julian; Bagshaw, Richard D.; Pawson, Tony; Emili, Andrew; Koninck, Yves De; Anggono, Victor; Airaksinen, Matti S.; Woodin, Melanie A.

doi:10.7554/elife.28270

Cited by 49 publications

(45 citation statements)

References 137 publications

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“…The specific gene networks altered by adolescent THC involved regulation of actin dynamics at excitatory synapses and dendritic spines, which recapitulates on a molecular level the morphological alterations . Notable genes with enhanced THC sensitivity included pyramidal-enriched Pacsin1, as well as Clu and Snap25, which are implicated in psychiatric diseases, such as schizophrenia and mood disorders (Wang et al, 2015;Pouget et al, 2016;Mahadevan et al, 2017). Intriguingly, the coordinated expression of genes altered by THC across development overlap with PFC gene expression networks dysregulated in humans with schizophrenia .…”

Section: Neurodevelopmental Thc Impacts the Epigenetic Landscape Relementioning

confidence: 99%

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

et al. 2019

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The recent shift in sociopolitical debates and growing liberalization of cannabis use across the globe has raised concern regarding its impact on vulnerable populations, such as pregnant women and adolescents. Epidemiological studies have long demonstrated a relationship between developmental cannabis exposure and later mental health symptoms. This relationship is especially strong in people with particular genetic polymorphisms, suggesting that cannabis use interacts with genotype to increase mental health risk. Seminal animal research directly linked prenatal and adolescent exposure to delta-9-tetrahydrocannabinol, the major psychoactive component of cannabis, with protracted effects on adult neural systems relevant to psychiatric and substance use disorders. In this article, we discuss some recent advances in understanding the long-term molecular, epigenetic, electrophysiological, and behavioral consequences of prenatal, perinatal, and adolescent exposure to cannabis/delta-9-tetrahydrocannabinol. Insights are provided from both animal and human studies, including in vivo neuroimaging strategies.

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Section: Neurodevelopmental Thc Impacts the Epigenetic Landscape Relementioning

confidence: 99%

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

et al. 2019

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“…), we have previously demonstrated that changes in E GABA can be detected using whole‐cell recordings (Ormond and Woodin, , Ormond and Woodin, , Takkala and Woodin, , Mahadevan et al . ). The use of the whole‐cell technique was necessary in the present study as a result of the longer‐term nature of the recordings, which required the washing‐in and ‐out of pharmacological agents, and the need to include a pharmacological agent in the recording pipette.…”

Section: Resultsmentioning

confidence: 98%

“…KCC2 has also been shown to physically interact with several excitatory receptors and proteins (Mahadevan et al . ), including the GluK2 subunit of kainate receptors (KARs) (Mahadevan et al . ), and the KAR auxiliary subunit Neto‐2 (Ivakine et al .…”

Section: Introductionmentioning

confidence: 99%

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

Garand

Mahadevan

Woodin

2019

The Journal of Physiology

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Key points Potassium‐chloride co‐transporter 2 (KCC2) plays a critical role in regulating chloride homeostasis, which is essential for hyperpolarizing inhibition in the mature nervous system. KCC2 interacts with many proteins involved in excitatory neurotransmission, including the GluK2 subunit of the kainate receptor (KAR). We show that activation of KARs hyperpolarizes the reversal potential for GABA (EGABA) via both ionotropic and metabotropic signalling mechanisms. KCC2 is required for the metabotropic KAR‐mediated regulation of EGABA, although ionotropic KAR signalling can hyperpolarize EGABA independent of KCC2 transporter function. The KAR‐mediated hyperpolarization of EGABA is absent in the GluK1/2−/− mouse and is independent of zinc release from mossy fibre terminals. The ability of KARs to regulate KCC2 function may have implications in diseases with disrupted excitation: inhibition balance, such as epilepsy, neuropathic pain, autism spectrum disorders and Down's syndrome. Abstract Potassium‐chloride co‐transporter 2 (KCC2) plays a critical role in the regulation of chloride (Cl−) homeostasis within mature neurons. KCC2 is a secondarily active transporter that extrudes Cl− from the neuron, which maintains a low intracellular Cl− concentration [Cl−]. This results in a hyperpolarized reversal potential of GABA (EGABA), which is required for fast synaptic inhibition in the mature central nervous system. KCC2 also plays a structural role in dendritic spines and at excitatory synapses, and interacts with ‘excitatory’ proteins, including the GluK2 subunit of kainate receptors (KARs). KARs are glutamate receptors that display both ionotropic and metabotropic signalling. We show that activating KARs in the hippocampus hyperpolarizes EGABA, thus strengthening inhibition. This hyperpolarization occurs via both ionotropic and metabotropic KAR signalling in the CA3 region, whereas it is absent in the GluK1/2−/− mouse, and is independent of zinc release from mossy fibre terminals. The metabotropic signalling mechanism is dependent on KCC2, although the ionotropic signalling mechanism produces a hyperpolarization of EGABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR:KCC2 complex may play an important role in excitatory:inhibitory balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signalling can regulate inhibition via multiple mechanisms. Activation of kainate‐type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during periods of strong glutamatergic activity.

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“…KCC2 interacts with a variety of transmembrane as well as intracellular partners, including postsynaptic receptors 44,45,46 , actin-related proteins 34,35,36 and others involved in protein trafficking and recycling 37 . Although these interactions are most often considered with regard to KCC2 expression or function, they also influence the function of KCC2 partners.…”

Section: Discussionmentioning

confidence: 99%

“…Through interactions with multiple transmembrane and intracellular partners, KCC2 was shown to regulate dendritic spine morphology 33,34 and actin cytoskeleton 35,36 , as well as the strength and long-term plasticity of glutamatergic synapses 33,35 . Recent functional proteomics data revealed additional putative KCC2 partners, including some involved in the recycling and trafficking of various transmembrane proteins and receptors 37 . Those may then either influence KCC2 function or, conversely, be regulated by KCC2.…”

Section: Introductionmentioning

confidence: 99%

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

Goutierre

Awabdh

François

et al. 2018

Preprint

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The K + /Cl − co-transporter KCC2 (SLC12A5) regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in several neurological and psychiatric disorders including epilepsy, neuropathic pain and autism spectrum disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents was depolarized in KCC2 knockdown neurons, this shift was fully compensated by depolarization of their resting membrane potential. This effect was due to downregulation of Task-3 leak potassium channels that we show require KCC2 for membrane trafficking. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis that could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that concur to perturb network activity, thus offering novel targets for therapeutic intervention.

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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Cited by 49 publications

References 137 publications

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

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Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

Cited by 49 publications

References 137 publications

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects

Ionotropic and metabotropic kainate receptor signalling regulates Cl− homeostasis and GABAergic inhibition

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

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Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition