Vignesh Subramanian ’24
A number of neurodegenerative disease processes, including those of temporal lobe epilepsy, GABA-transaminase deficiency, and traumatic brain injury, involve disruptions to the signalling pathway of gamma-aminobutyric acid (GABA), the chief inhibitory neurotransmitter of the central nervous system. Conventional understanding divides the ability of GABA to block neural signaling into ‘presynaptic inhibition’ – involving suppression of glutamate release, an excitatory counterpart neurotransmitter – and ‘postsynaptic inhibition’, involving changes in electrical conductance along membrane potentials. These functions are enabled by the presence of GABAB and GABAA receptors at presynaptic and postsynaptic terminals, respectively. However, evidence of GABAA receptor presence at presynaptic terminals in the hippocampus, sensory neocortex, and cerebellum suggests long-term potentiation between neurons may be regulated at alternative sites of action. To establish whether such presynaptic inhibition at GABAA receptors rather than GABAB may also be possible in neocortical circuits (those concerning higher cognitive functioning), Stony Brook researcher Dr. Arianna Maffei and her team examined evoked inhibitory currents in Layer 4 (L4) of the rat primary visual cortex (V1) to determine the effects of GABAA receptor agonists.
Researchers first immersed V1-containing acute coronal slices of P14 rats in bath applications of drugs diazepam (DZ) and muscimol (Mus), both GABAA receptor agonists, and collected patch clamp recordings of signaling between subjects’ pyramidal (Pyr) and fast spiking (FS) neurons, which conduct thalamocortical (TC) (visual, somatic, and auditory) inputs. Terminal field photostimulation and coimmunostaining protocols were then applied to neuronal axons in the lateral geniculate nucleus – a specific cortical region communicating with L4 neurons – and selectively expressed neurotransmitter transporters to determine effects on signal potentiation and receptor localization.
It was found that Mus-sensitive GABAA receptors insensitive to DZ binding were capable of modulating the amplitude and variation of excitatory currents at FS and Pyr neurons, and that Mus-induced local reduction of inhibitory currents could presynaptically occur. The data also demonstrated how the puncta of presynaptic GABAA receptors capable of decreasing TC transmission could be detected at TC terminals in V1, as well as how bursts of inhibitory neuron-fired GABA could be correlated with immediate suppression of excitatory potentiation.
The findings of this study substantiate the presence of presynaptic GABAA receptors capable of blocking TC transmission both locally and in response to afferent inputs in L4 of the primary visual cortex. The novel knowledge that such receptors exist in neocortical circuits underscores the existence of alternative mechanisms by which overstimulation from neurodegenerative disorders can be pharmacologically counteracted.
 A. Maffei, et al., Presynaptic GABAA Receptors Modulate Thalamocortical Inputs in Layer 4 of Rat V1. Cerebral Cortex (Oxford Academic) 29, 921-936 (2019). doi: 10.1093/cercor/bhx364
 Image retrieved from: https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid#/media/File:GABA_3D_ball.png