Regulation of cortical microcircuits by unitary GABA-mediated volume transmission

Abstract

Gamma-aminobutyric acid (GABA) 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 inhibition2–4. 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 GABA3–7. The synaptic and extrasynaptic action of GABA is in line with idea that neurons of the brain use synaptic (or wiring) transmission and nonsynaptic (or volume) transmission for communication8,9. However, reuptake mechanisms restrict the spatial extent of extrasynaptic GABAergic effects10,11 and it was proposed that concerted action of several presynaptic interneurons or sustained firing of individual cells or increased release site density is required to reach ambient GABA levels sufficient to activate extrasynaptic receptors4,9,11–13. Here we show that individual neurogliaform cells release GABA sufficient for volume transmission within the axonal cloud and thus 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 which do not receive synapses at all in the cerebral cortex and, moreover, reach extrasynaptic, δ subunit containing GABAA (GABAAδ) receptors responsible for tonic inhibition. We reveal that GABAAδ receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABAAδ receptors, alter unitary GABAergic 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 spatial unspecificity in GABAergic systems leading to long lasting network hyperpolarization combined with widespread suppression of communication in the local circuit.

Postnatal Switch from Synaptic to Extrasynaptic Transmission between Interneurons and NG2 Cells

“…Ultrastructural analyses of climbing fiber terminals and molecular layer interneurons have shown tight membrane appositions external to but in the region of active zones (Kollo et al, 2006), which provides an indirect morphological support for glutamate spillover transmission at these particular junctions. In addition, a recent report showed that cortical neurogliaform interneurons do not require direct synaptic junctions to induce unitary GABAmediated responses in target neurons (Olah et al, 2009), corroborating our evidence that pure spillover connections may constitute a precise phasic mode of communication between interneurons and NG2 cells in the mature brain.…”

“…Recently, an unusual mechanism of pure spillover transmission that induce phasic responses in the absence of classical synaptic activity has been described for neuronal connections in the cerebellum (Szapiro and Barbour, 2007) and the neocortex (Olah et al, 2009). By using pharmacological agents, we tested whether this mode of neuronal communication also controls GABAergic transmission from interneurons to NG2 cells in the barrel cortex after the second PN week.…”

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

“…It should also be emphasized that perisomatic interneurones establish several thousand terminals at a density of approx. 80 per 100 μm 3 (Oláh et al, 2009), a value that is much higher than what reported for principal cells (cf. for CA3 pyramidal cells Wittner and Miles, 2007).…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Another type of basket cells, containing CCK, also form perisomatic contacts onto pyramidal cells; however, they are distinguished from the PV þ variety by their slower, accommodating firing patterns (Hefft and Jonas, 2005) that integrate neuromodulatory information with faster network activity (Freund, 2003;Varga et al, 2009). Interconnected networks of NPY þ neurogliaform cells mediate regional tonic inhibition through extrasynaptic volume transmission in multiple cortical and subcortical regions (Manko et al, 2012;Olah et al, 2009;Price et al, 2005). Martinotti cells, containing CR, CB, SST, NPY, and/or CCK, span both cortical lamina and cortical columns and synapse onto pyramidal cell tuft dendrites in layer I (Markram et al, 2004).…”