Axons in the cerebral cortex receive synaptic input at the axon initial segment almost exclusively from gamma-aminobutyric acid-releasing (GABAergic) axo-axonic cells (AACs). The axon has the lowest threshold for action potential generation in neurons; thus, AACs are considered to be strategically placed inhibitory neurons controlling neuronal output. However, we found that AACs can depolarize pyramidal cells and can initiate stereotyped series of synaptic events in rat and human cortical networks because of a depolarized reversal potential for axonal relative to perisomatic GABAergic inputs. Excitation and signal propagation initiated by AACs is supported by the absence of the potassium chloride cotransporter 2 in the axon.

Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

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.

Banyan Biomarkers and US Army Medical Research and Materiel Command.

In November 2017, the Lancet Neurology Commission on Traumatic Brain Injury (TBI) highlighted existing deficiencies in epidemiology, patient characterization, identifying best practice, outcome assessment, and evidence generation. The Commission concluded that C needed to address deficiencies in prevention , and made a recommendation for large collaborative studies which could provide the framework for precision medicine and comparative effectiveness research (CER).