GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition

Jacob, Tija C.; Moss, Stephen J.; Jurd, Rachel

doi:10.1038/nrn2370

Cited by 594 publications

(585 citation statements)

References 146 publications

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“…Unexpectedly, although the ErbB4 receptor is essential for reducing the mIPSCs in response to NRG2, its canonical receptor tyrosine kinase (RTK) activity is entirely dispensable. Our results are consistent with other studies suggesting a model for extrasynaptic GABAR trafficking (25)(26)(27)(28), and they introduce NRG-ErbB4 signaling as a critical modulator of postsynaptic GABAR signaling in interneurons.…”

supporting

confidence: 83%

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

Mitchell

Janssen

Karavanova

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy. In cortical tissue, ErbB4 associates with excitatory synapses located on inhibitory interneurons. However, biochemical and histological data described herein demonstrate that the vast majority of ErbB4 is extrasynaptic and detergent-soluble. To explore the function of this receptor population, we used unbiased proteomics, in combination with electrophysiological, biochemical, and cell biological techniques, to identify a clinically relevant ErbB4-interacting protein, the GABA A receptor α1 subunit (GABAR α1). We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR α1 expression. Moreover, we characterize a Neuregulin-mediated ErbB4 signaling modality, independent of receptor tyrosine kinase activity, that couples ErbB4 to decreased postsynaptic GABAR currents on inhibitory interneurons. Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR α1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin. Our results reveal a function of ErbB4, independent of its tyrosine kinase activity, that modulates postsynaptic inhibitory control of hippocampal interneurons and may provide a novel pharmacological target in the treatment of neuropsychiatric disorders and epilepsy.PKC | schizophrenia | hippocampus | parvalbumin | mIPSCs E rbB4 signaling regulates neuronal excitability (1, 2) and synaptic plasticity (3, 4) in the adult brain, and has been implicated in psychiatric disorders (5, 6) and epilepsy (2, 7). In the neocortex and hippocampus of rodents, monkeys, and humans, ErbB4 expression is restricted to GABAergic interneurons, and its expression is particularly high in parvalbumin-positive fastspiking (PV+) interneurons (8, 9). Of note, targeted ablation of ErbB4 specifically in PV+ interneurons recapitulates behavioral abnormalities of full ErbB4-null mice, highlighting the importance of ErbB4 signaling in this GABAergic interneuron subclass (10). Moreover, gamma oscillations, a type of high-frequency network activity that depends on synchronization of local circuits by PV+ interneurons, are augmented by Neuregulin (NRG)1 in vitro in an ErbB4-dependent manner (11).In the hippocampus, the GABA A receptor α1 subunit (GABAR α1), which imparts rapid decay kinetics (12), is also selectively expressed in subsets of inhibitory interneurons, especially in PV+ neurons (13,14). Furthermore, a mutation in GABRA1 has been linked to absence seizures (15), and heterozygous Gabra1-null mice show cortical absence epileptiform activity (16). Additionally, genome-wide linkage analyses have repeatedly identified a cluster of GABAR subunits, which includes GABRA1, as a schizophrenia (SCZ) susceptibility locus (17). Therefore, identifying mechanisms that acutely regulate α1-containing GABARs o...

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supporting

confidence: 83%

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

Mitchell

Janssen

Karavanova

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…1, ionotropic GABA A receptors in mammals are heteropentameric molecules formed from a family of at least 19 related subunits named α (six varieties identified as 1-6), β (1-4), γ (1-3), δ, ε, π and ρ (1-3) plus a few splice variants (Burt and Kamatchi, 1991;Macdonald and Olsen, 1994;Olsen and Macdonald, 2002;Kaila, 1994;Bormann, 2000;Farrant and Kaila, 2007;Jacob et al, 2008;Olsen and Sieghart, 2008). GABA A receptors with different subunit composition have specific functional and pharmacological characteristics and are differentially expressed in various regions of the brain.…”

Section: Gaba As a Transmitter At Central Synapsesmentioning

confidence: 99%

“…Note that: (i) the extracellular amino terminus is the site of GABA binding, and also contains binding sites for psychoactive drugs, such as benzodiazepines; (ii) the large intracellular loop between TM3 and TM4 (P) is the site for various protein interactions as well as for various posttranslational modifications that modulate receptor activity. Panels in this figure were drawn according to information obtained from Bormann (2000) and Jacob et al (2008). Reconstruction of the dendritic and axonal arbour of a biocytin-filled presumptive interneuron.…”

Section: Apmentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

224

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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“…The anxiolytic-like activity of PGE 2 is associated with the activation of serotonin 5-HT 1A , dopamine D 1 and GABA A receptors Next, we investigated mediators associated with the anxiolyticlike activity of PGE 2 . Serotonin 5-HT 1A , dopamine D 1 and GABA A receptors are known to be involved in anxiolytic-like activity in animals and humans [21,[23][24][25]; thus, we investigated whether these receptors were involved in the anxiolytic-like activity of PGE 2 using antagonists for them.…”

Section: Activation Of Ep 1 /Ep 4 Receptors Exhibits Anxiolytic-likementioning

confidence: 99%

Central PGE₂exhibits anxiolytic-like activity via EP₁and EP₄receptors in a manner dependent on serotonin 5-HT_1A, dopamine D₁and GABA_Areceptors

et al. 2011

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a b s t r a c tWe found that centrally administered prostaglandin (PG) E 2 exhibited anxiolytic-like activity in the elevated plus-maze and open field test in mice. Agonists selective for EP 1 and EP 4 receptors, among four receptor subtypes for PGE 2 , mimicked the anxiolytic-like activity of PGE 2 . The anxiolytic-like activity of PGE 2 was blocked by an EP 1 or EP 4 antagonist, as well as in EP 4 but not EP 1 knockout mice. Central activation of either EP 1 or EP 4 receptors resulted in anxiolytic-like activity. The PGE 2 -induced anxiolytic-like activity was inhibited by antagonists for serotonin 5-HT 1A , dopamine D 1 and GABA A receptors. Taken together, PGE 2 exhibits anxiolytic-like activity via EP 1 and EP 4 receptors, with downstream involvement of 5-HT 1A , D 1 and GABA A receptor systems.

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GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition

Cited by 594 publications

References 146 publications

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Central PGE₂exhibits anxiolytic-like activity via EP₁and EP₄receptors in a manner dependent on serotonin 5-HT_1A, dopamine D₁and GABA_Areceptors

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GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition

Cited by 594 publications

References 146 publications

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Central PGE2exhibits anxiolytic-like activity via EP1and EP4receptors in a manner dependent on serotonin 5-HT1A, dopamine D1and GABAAreceptors

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ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

ErbB4 reduces synaptic GABA _A currents independent of its receptor tyrosine kinase activity

Central PGE₂exhibits anxiolytic-like activity via EP₁and EP₄receptors in a manner dependent on serotonin 5-HT_1A, dopamine D₁and GABA_Areceptors