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Regulation of cortical microcircuits by unitary GABA-mediated volume transmission


GABA (γ-aminobutyric acid) is predominantly released by local interneurons in the cerebral cortex to particular subcellular domains of the target cells1,2. This suggests that compartmentalized, synapse-specific action of GABA is required in cortical networks for phasic inhibition2,3,4. However, GABA released at the synaptic cleft diffuses to receptors outside the postsynaptic density and thus tonically activates extrasynaptic GABAA and GABAB receptors, which include subtypes of both receptor families especially sensitive to low concentrations of GABA3,4,5,6,7. The synaptic and extrasynaptic action of GABA corroborates the idea that neurons of the brain use synaptic (or wiring) transmission and non-synaptic (or volume) transmission for communication8,9. However, re-uptake mechanisms restrict the spatial extent of extrasynaptic GABA-mediated effects10,11, and it has been proposed that the concerted action of several presynaptic interneurons, the sustained firing of individual cells or an increase in release-site density is required to reach ambient GABA levels sufficient to activate extrasynaptic receptors4,9,11,12,13. Here we show that individual neurogliaform cells release enough GABA for volume transmission within the axonal cloud and, thus, that neurogliaform cells do not require synapses to produce inhibitory responses in the overwhelming majority of nearby neurons. Neurogliaform cells suppress connections between other neurons acting on presynaptic terminals that do not receive synapses at all in the cerebral cortex. They also reach extrasynaptic, δ-subunit-containing GABAA (GABA) receptors responsible for tonic inhibition. We show that GABA receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABA receptors, alter unitary GABA-mediated effects between neurogliaform cells. In contrast to the specifically placed synapses formed by other interneurons, the output of neurosteroid-sensitive neurogliaform cells represents the ultimate form of the lack of spatial specificity in GABA-mediated systems, leading to long-lasting network hyperpolarization combined with widespread suppression of communication in the local circuit.

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Figure 1: Neurogliaform cells do not require direct synaptic junctions to affect target cells.
Figure 2: Heterosynaptic or paracrine effects of neurogliaform cells on axons of other neurons.
Figure 3: Extrasynaptically placed GABA receptors are localized to neurogliaform cells and targeted by GABA released from neurogliaform cells.


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The authors thank W. Sieghart for donating antibody, A. Lőrincz and Z. Nusser for initial testing of the GABA antibody, I. Mody for the GABA -/- animals, and A. Simon and E. Tóth for reconstructions. This work was supported by the European Young Investigator Award, the Hungarian National Office for Research and Technology Polányi Award, the Howard Hughes Medical Institute, US National Institutes of Health grant NS535915, the Boehringer Ingelheim Fonds and the Hungarian Academy of Sciences.

Author Contributions S.O. performed experiments, analysed data and wrote the paper; M.F., G.K., C.V. and R.B. performed experiments and analysed data; P.B. performed experiments; and G.T. designed and performed experiments, analysed data and wrote the paper.

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Correspondence to Gábor Tamás.

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Oláh, S., Füle, M., Komlósi, G. et al. Regulation of cortical microcircuits by unitary GABA-mediated volume transmission . Nature 461, 1278–1281 (2009).

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