Scientific Understanding of Consciousness
Nature 461, 1278-1281 (29 October 2009)
Regulation of cortical microcircuits by unitary GABA-mediated volume transmission
Szabolcs Oláh1, Miklós Füle1, Gergely Komlósi1, Csaba Varga1, Rita Báldi1, Pál Barzó2 & Gábor Tamás1
Research Group for Cortical Microcircuits of the Hungarian Academy of Sciences, Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, Szeged H-6726, Hungary
Department of Neurosurgery, University of Szeged, Semmelweis utca 6, Szeged H-6725, Hungary
Uniquely among neocortical interneurons, neurogliaform cells evoke long-lasting inhibition in the form of an unusually slow GABAA-receptor-mediated component and slow GABAB-receptor-mediated responses in their target neurons. A distinctive feature of neurogliaform cells among cortical interneurons is that they have very dense axonal arborizations, in which presynaptic boutons on the same or neighbouring axon collaterals can be found a couple of micrometres from each other. GABA can activate receptors located up to several micrometres from the release site. We measured the density of terminals in neurogliaform-cell (n = 8) and basket-cell (n = 6) axons (421,213 34,289 and 78,506 8,423 boutons per cubic millimetre, respectively; P < 0.0001) and found that a single neurogliaform-cell axon matches the potential release-site density of five or six overlapping basket-cell axons. We proposed that the high density of neurogliaform-cell axons could counteract transmitter re-uptake mechanisms and that GABA released from neurogliaform cells acts as a volume transmitter to reach receptors at synaptic and non-synaptic sites in the tissue the axon intermingles with.
Potential volume transmission suggests a very high rate of functional coupling between neurogliaform cells and neighbouring neurons. We confirmed the presence of gap junctions in which electrical coupling potentials were recorded in addition to inhibitory postsynaptic potentials (IPSPs), even though ultrastructural identification of gap junctions between labelled neurons is more difficult than that of synapses. The majority (78%) of neurogliaform-cell axonal varicosities do not form classical synapses. These results suggest that neurogliaform-cell axons do not necessarily require a synaptic contact to elicit inhibitory responses in target cells.
Although suspected non-synaptic communication by neurogliaform cells is consistent with the lack of detectable synapses, positive evidence is required to prove the volume transmission hypothesis. We confirmed that neocortical neurogliaform cells modulate their own axon terminals by means of GABAB receptors similar to hippocampal neurogliaform cells.
Unlike other interneuron types that specifically place synapses on particular compartments of postsynaptic cells, neurogliaform cells provide non-synaptic, spatially non-specific input to the entire surface of target cells, complementing conventional synapses. Neurogliaform cells release GABA, covering their axonal fields in effective concentrations, and target the overwhelming majority of nearby neurons, which selectively express receptors sensitive to low concentrations of the neurotransmitter on their various compartments. Although presynaptic mechanisms producing the GABA cloud around neurogliaform axons are not understood, they might involve a unique release mechanism with an unconventional calcium dependence. Provided that release and re-uptake mechanisms are similar, local GABA concentrations produced by distinct interneurons probably emerge at distances of about half the inter-terminal distance, meaning that basket cells should be less effective than neurogliaform cells around 3 m from their terminals. The spatial extent of axons suggests that neurogliaform cells provide a means of making synchronized changes in the efficacy of synaptic connections in conjunction with regulating dendritic excitability across distances of around 200 m.
In certain operational states of the microcircuit, solitary spikes in a single neurogliaform cell might replace the concerted action potentials of interneuron populations in modulating presynaptic terminals and postsynaptic domains expressing GABA receptors.