Regulation of cortical microcircuits by unitary GABA-mediated volume transmission

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
Many receptors for neurotransmitters are found outside neuronal synapses and can be activated by excess neurotransmitter spilling out of the synaptic cleft. But neurotransmitter reuptake by extrasynaptic transporters has been thought to limit the significance of such extrasynaptic signals. Now Tamás and colleagues show that a poorly described cell type of the cerebral cortex, the neurogliaform cells, release the inhibitory neurotransmitter GABA as a large and dense cloud and thus do not require synapses to produce inhibitory responses in the vast majority of neighbouring neurons. They further show that neurosteroids suppress these neurogliaform cells' excitability, which may explain the role of these hormones in post-partum depression and premenstrual syndrome. Excess neurotransmitter diffuses out of the synaptic cleft, where it can activate neurotransmitter receptors outside the postsynaptic density. However, neurotransmitter reuptake is thought to limit the significance of such extrasynaptic, or 'volume', transmission. Individual neurogliaform cells are now shown to release enough GABA for volume transmission within the axonal cloud; these cells do not require synapses to produce inhibitory responses in nearby neurons. 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 (GABAAδ) receptors responsible for tonic inhibition. We show that GABAAδ receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABAAδ 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.