4 November 2009. In the grand spectacle of neuronal communication, there is a new player on the scene: neurogliaform cells. Known for their distinctive web-like shape, neurogliaform cells belong to the diverse panoply of inhibitory interneurons that dampen electrical signaling using the neurotransmitter GABA (Markram et al., 2004). But as shown in a new paper in Nature, these neurogliaform cells act outside of synapses, the usual connecting points between neurons, and instead dump their GABA into the extracellular space to evoke inhibitory responses in nearby neurons. This kind of "volume transmission"—as opposed to synaptic transmission—provides another way for GABA to influence cortical circuits, a possibility worth bearing in mind in light of the disrupted inhibitory networks proposed to underlie some aspects of schizophrenia (Lewis et al., 2005).

Led by Gábor Tamás at the University of Szeged in Hungary, the researchers reasoned that neurogliaform cells were well suited for volume transmission because their axons, which branch profusely and have a high density of GABA release sites, seemed capable of producing a cloud of GABA that can impinge upon nearby neurons. Despite finding ample electrophysiological evidence for neurogliaform cell inhibition of nearby neurons, the team was unable to locate much in the way of actual synaptic contacts along neurogliaform axons using electron microscopy. This suggested that the neurogliaform cells didn't need the traditional synapse to inhibit other cells.

To test for this, first author Szabolcs Oláh and colleagues asked whether neurogliaform cells could activate GABA receptors located outside of a synapse. These seemingly orphaned extra-synaptic GABA receptors are found on the presynaptic terminals of glutamate-containing excitatory neurons in the cortex, and the only way they can be activated is when GABA happens to drift over to them. Using simultaneous triple neuron recordings—one electrode in a glutamatergic neuron, another in the neuron it synapses onto, and a third in a nearby neurogliaform cell (not for the faint-hearted!)—the team showed that activation of the neurogliaform cell suppressed the amplitude of the signals passing from the glutamatergic neuron to its post-synaptic neuron, and that at least part of this suppression resulted from activation of the extra-synaptic GABA receptors. Thus, in addition to provoking inhibitory responses in nearby neurons, neurogliaform cells can stifle the signals passing between two synaptically coupled neurons.

Detail from Figure 3a of Oláh et al. "GABA_Aδ-receptor immunoreaction on a simultaneously recorded and biocytin-filled neurogliaform cell (NGF) and postsynaptic interneuron (INT). GABA_Aδ receptors were detected on the neurogliaform cell only." [Image credit: Authors and Nature Journals]

Neurogliaform cells themselves are also targets of volume transmission, and bear extra-synaptic GABA receptors, Oláh and colleagues found. When one neurogliaform cell is activated, a neighbor experiences a sizeable inhibitory hyperpolarization. The receptors on these cells were found to be of the GABA_Aδ subtype, and neurogliaform cells were unusual among interneurons in their expression of these. This raised the possibility of manipulating neurogliaform cells with neurosteroids, which target GABA_Aδ receptors. Indeed, when the neurosteroid THDOC was applied, the neurogliaform cells were less excitable, and their responses to GABA released from a neighbor neurogliaform cell were enhanced.

Dumping GABA over a relatively large space in the brain, rather than dispensing it in discrete pulses across the synapse, provides a new way of making synchronized changes to various parts of a cortical circuit, something that was previously thought to require the concerted action of multiple interneurons using synapses. With volume transmission, then, a single spike from a small neurogliaform cell may be able to shift the balance of activity across a neural circuit. While it is not known when neurogliaform cells are normally activated, and whether they are perturbed in brain disorders like schizophrenia, they bring a new mode of inhibition into consideration when figuring out how neural circuits function in health and disease.—Michele Solis.

Reference:
Oláh S, Füle M, Komlósi G, Varga C, Báldi R, Barzó P, Tamás G. Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature. 2009 Oct 29; 461: 1278-1281. Abstract