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Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

ABSTRACT: The lateral mobility of neurotransmitter receptors has been shown to tune synaptic signals. Here we report that GABAA receptors (GABAARs) can diffuse between adjacent dendritic GABAergic synapses in long-living desensitized states, thus laterally spreading "activation memories" between inhibitory synapses. Glutamatergic activity limits this inter-synaptic diffusion by trapping GABAARs at excitatory synapses. This novel form of activity-dependent hetero-synaptic interplay is likely to modulate dendritic synaptic signaling.

SUBMITTER: de Luca E

PROVIDER: S-EPMC5500312 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

de Luca Emanuela E Ravasenga Tiziana T Petrini Enrica Maria EM Polenghi Alice A Nieus Thierry T Guazzi Stefania S Barberis Andrea A

Neuron 20170701 1

The lateral mobility of neurotransmitter receptors has been shown to tune synaptic signals. Here we report that GABAA receptors (GABAARs) can diffuse between adjacent dendritic GABAergic synapses in long-living desensitized states, thus laterally spreading "activation memories" between inhibitory synapses. Glutamatergic activity limits this inter-synaptic diffusion by trapping GABAARs at excitatory synapses. This novel form of activity-dependent hetero-synaptic interplay is likely to modulate de ...[more]

PMID: 28683270

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Project description:GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 µM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN.NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock.

Dataset Information

Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

Publications

Inter-Synaptic Lateral Diffusion of GABAA Receptors Shapes Inhibitory Synaptic Currents.

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