Functional Correlation of GABA<sub>A</sub>Receptor α Subunits Expression with the Properties of IPSCs in the Developing Thalamus

Okada, Masayoshi; Onodera, Kayoko; Renterghem, Catherine Van; Sieghart, Werner; Takahashi, Tomoyuki

doi:10.1523/jneurosci.20-06-02202.2000

Cited by 136 publications

(149 citation statements)

References 33 publications

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“…4 C and D) in ErbB4+ interneurons, consistent with a reduction of rapidly decaying synaptic currents. Because GABAR α1 confers rapid decay kinetics (12,34,35), our results indicate that NRG2-ErbB4 association preferentially targets synaptic α1 subunit-containing GABARs.…”

Section: ) (E) Representativementioning

confidence: 79%

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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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Section: ) (E) Representativementioning

confidence: 79%

“…4E, NRG2 results in phosphoactivation of PKCγ but not PKCα/βII. To selectively block PKC activation, we included an inhibitory PKC (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) peptide (10 μM) in the intracellular solution. As illustrated in Fig.…”

Section: Nrg2 Alters Gabar Currents Through Clathrin-dependent Endocymentioning

confidence: 99%

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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“…Developmental speeding in the decay time of synaptic currents is commonly observed at both excitatory (Sakmann and Brenner, 1978;Fischbach and Schuetze, 1980) and inhibitory (Takahashi et al, 1992;Okada et al, 2000) synapses. At the excitatory synapse, speeding of the synaptic current decay contributes to faster rising EPSPs and reduced spike jitter, thereby increasing the temporal precision of synaptic transmission (Galarreta and Hestrin, 2001;Cathala et al, 2003), which is essential for accurate sensory perceptions, organized motor movements, and cognition.…”

Section: Introductionmentioning

confidence: 99%

“…At the excitatory synapse, speeding of the synaptic current decay contributes to faster rising EPSPs and reduced spike jitter, thereby increasing the temporal precision of synaptic transmission (Galarreta and Hestrin, 2001;Cathala et al, 2003), which is essential for accurate sensory perceptions, organized motor movements, and cognition. Developmental switches of postsynaptic receptor subunits underlie speeding in the decay time of synaptic currents mediated by nicotinic acetylcholine receptors (Mishina et al, 1986), glycine receptors (Takahashi et al, 1992), GABA A receptors (Okada et al, 2000), and NMDA receptors (NMDARs) Takahashi et al, 1996). Like other synaptic currents, the decay time of AMPA-EPSCs at the calyx of Held becomes faster during postnatal development (Taschenberger and von Gersdorff, 2000;Futai et al, 2001;Iwasaki and Takahashi, 2001;Joshi and Wang, 2002;Wall et al, 2002;Yamashita et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held

Koike-Tani

Saitoh²,

Takahashi³

2005

J. Neurosci.

116

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The time course of synaptic conductance is important in temporal precision of information processing in the neuronal network. The AMPA receptor (AMPAR)-mediated EPSCs at the calyx of Held become faster in decay time as animals mature. To clarify how desensitization and deactivation of AMPARs contribute to developmental speeding of EPSCs, we compared the decay time of quantal EPSCs (qEPSCs) with the deactivation and desensitization times of AMPAR currents induced in excised patches by fast glutamate application (AMPA patch currents). Both the deactivation and desensitization times of AMPA patch currents became markedly faster from postnatal day 7 (P7) to P14 and changed little thereafter. In individual neurons, throughout development (P7-P21), the time constants of deactivation and fast desensitization in AMPA patch currents were similar to each other and close to the qEPSC decay time constant. Cyclothiazide (CTZ) abolished the fast desensitization, prolonged deactivation of AMPA patch currents, and slowed the decay time of EPSCs. The effects of CTZ on AMPA patch currents were unchanged throughout development, whereas its effect on EPSCs became weaker as animals matured. In single-cell reverse transcription-PCR analysis, glutamate receptor subunit 4 (GluR4) flop increased from P7 to P14 and changed little thereafter. At P7, the GluR4 flop abundance had an inverse correlation with the qEPSC decay time. These results together suggest that both desensitization and deactivation of AMPARs are involved in the EPSC decay time, but the contribution of desensitization decreases during postnatal development at the calyx of Held.

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“…During development, the subunit composition and expression of GABA receptors undergo changes. However, there is high expression of thalamic GABA receptors at postnatal day 14 Okada et al 2000). The principal GABA A subunit transcripts, ␣ 1 , ␣ 4 , ␤ 2 , and ␦ mRNA, reach adult levels in the thalamus of rats by P12 Wisden et al 1992).…”

Section: Depressant Effects During Gaba Receptor Blockadementioning

confidence: 99%

Pentobarbital Depressant Effects Are Independent of GABA Receptors in Auditory Thalamic Neurons

Wan

Puil

2002

Journal of Neurophysiology

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Pentobarbital, a general anesthetic, has received extensive study for its ability to potentiate inhibition at GABAA subtype of receptors for GABA. Using whole cell current-clamp techniques and bath applications, we determined the effects of pentobarbital and GABA receptor antagonists on the membrane properties and tonic or burst firing of medial geniculate neurons in thalamic slices. Pentobarbital (0.01–200 μM) induced depressant effects in 50 of 66 neurons (76%). Pentobarbital hyperpolarized neurons by a mean of 3 mV and decreased the number of action potentials in tonic firing, evoked by current pulse injection from near the resting potential. Pentobarbital also decreased burst firing or low threshold Ca2+-spikes, evoked by current pulse injection into neurons at potentials hyperpolarized from rest. The blockade of tonic and burst firing, as well as low threshold Ca2+-spikes, was surmountable by increasing the amplitude of input current. The GABAA receptor antagonists, bicuculline (100 μM) and picrotoxinin (50–100 μM), did not block the depressant effects of pentobarbital (10 μM). The GABAB receptor antagonist, saclofen (200 μM), and GABAC receptor antagonist, (1,2,3,6-tetrahydropyridine-4-yl)methylphosphinate (10–50 μM), did not significantly alter the depressant effects. Pentobarbital produced excitatory effects (0.1–50 μM) on 11 neurons (17%) but had no effects on 5 neurons (7%). The excitation consisted of approximately 3 mV depolarization, increased tonic and burst firing and the rate of rise and amplitude of low threshold Ca2+ spikes. These effects were associated with a increase in input resistance. In contrast, the depressant effects of pentobarbital correlated to a decreased input resistance measured with hyperpolarizing current pulse injection (IC50 = 7.8 μM). Pentobarbital reduced Na+-dependent rectification on depolarization and lowered the slope resistance over a wide voltage range. Tetrodotoxin eliminated both Na+-dependent rectification and the pentobarbital-induced decrease in membrane resistance at depolarized voltages in two-thirds of the neurons. The pentobarbital-induced decrease in membrane resistance at voltages hyperpolarized from rest was not evident during co-application with Cs+, known to block the hyperpolarization-activated rectifiers. In summary, the pentobarbital acted at low concentrations to depress thalamocortical neurons. The depression resulted from decreased rectification on depolarization, which no longer boosted potentials over threshold, and an increased conductance that shunted spike generation. The depressant effects of pentobarbital did not involve known types of GABA receptor interactions.

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Functional Correlation of GABA_AReceptor α Subunits Expression with the Properties of IPSCs in the Developing Thalamus

Cited by 136 publications

References 33 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

Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held

Pentobarbital Depressant Effects Are Independent of GABA Receptors in Auditory Thalamic Neurons

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Functional Correlation of GABAAReceptor α Subunits Expression with the Properties of IPSCs in the Developing Thalamus

Cited by 136 publications

References 33 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

Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held

Pentobarbital Depressant Effects Are Independent of GABA Receptors in Auditory Thalamic Neurons

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Product

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Functional Correlation of GABA_AReceptor α Subunits Expression with the Properties of IPSCs in the Developing Thalamus

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