New study from the Akerman group shows that synaptic inhibition changes dynamically to match brain state

Synaptic inhibition plays a fundamental role in brain function as it determines how we respond to sensory stimuli, process information, and control our body movements. In our cortex for example, synaptic inhibition is mediated by GABA_A receptors, which are activated by the neurotransmitter GABA and are mainly permeable to chloride ions. Textbooks typically describe synaptic inhibition as having a hyperpolarizing effect on neurons by causing influxes of chloride ions. However, this has been an assumption based on recordings conducted in vitro, or where the recording method alters the ion gradients that underpin synaptic inhibition. Therefore, despite their fundamental role, a long-standing question in the field has been how do GABA_A receptors signal in the intact brain?

A team of scientists at the University of Oxford led by Professor Colin Akerman (Department of Pharmacology), have addressed this problem through a technical tour de force, by being the first to apply a technique called gramicidin perforated patch recordings in vivo. Gramicidin recordings preserve transmembrane chloride gradients, making it possible to compare synaptic inhibition under undisturbed conditions and across different brain states. Through this breakthrough, the team reveal that the way synaptic inhibition operates in cortical neurons is dynamic and closely linked to the levels of activity across the entire network of neurons. Under anesthetized conditions, when the network is relatively quiet, activating synaptic GABA_A receptors results in membrane hyperpolarization because the equilibrium for the GABA_A receptor is more negative than the membrane’s voltage. In the awake state however, activation of synaptic GABA_A receptors results in a phenomenon known as “shunting inhibition” in which the inhibitory effects are mediated by local effects on the membrane resistance, rather than on membrane voltage. The shunting nature of synaptic GABA_AR signalling results from the high levels of network activity that characterize the awake state, and which are shown to cause the equilibrium for the GABA_A receptor to move much closer to the membrane voltage. This begged the question: why does the awake cortex preferentially utilize shunting inhibition? The team answered this by showing that the switch from hyperpolarizing to shunting synaptic inhibition has profound implications for how the cortex responds to stimuli. Synaptic inhibition in the awake state helps to desynchronize neighboring cortical neurons, which increases their flexibility in responding to incoming information. In essence, GABA_AR signaling is dynamic and adapts to optimize cortical functions depending on the state of the brain.

The paper is first authored by Dr Richard Burman and Dr Paul Brodersen and is published this week in Neuron. The full paper is entitled “Active cortical networks promote shunting fast synaptic inhibition in vivo” and is available to read here:

https://www.cell.com/neuron/fulltext/S0896-6273(23)00586-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS089662732300586X%3Fshowall%3Dtrue