Suppressing astrocytic GABA transaminase enhances tonic inhibition and weakens hippocampal spatial memory

Abstract

Pharmacological suppression of γ-aminobutyric acid (GABA) transaminase (GABA-T), the sole GABA-degrading enzyme and a potential therapeutic target for treating brain disorders such as epilepsy, increases not only phasic inhibition but also tonic inhibition. However, the specific cellular source, neuromodulatory effects and potential therapeutic benefits of this enhanced tonic inhibition remain unexplored due to the lack of cell-type-specific gene manipulation studies. Here we report that the increase in tonic GABA currents observed after GABA-T suppression is predominantly due to increased tonic GABA release from astrocytes rather than action-potential-dependent synaptic GABA spillover. General GABA-T knockdown (KD) by a short hairpin RNA considerably increased tonic GABA currents in dentate granule cells, thereby enhancing tonic inhibition. An astrocyte-specific rescue of GABA-T following general GABA-T KD normalized the elevated tonic GABA currents to near control levels. Tetrodotoxin-insensitive tonic GABA currents were significantly increased after general GABA-T KD, whereas tetrodotoxin-sensitive tonic GABA currents showed no significant increase, suggesting that this enhanced tonic inhibition is primarily action-potential independent. General GABA-T KD reduced the spike probability of granule cells and impaired dorsal hippocampus-dependent spatial memory, which were fully reversed by astrocyte-specific GABA-T rescue. These findings suggest that suppressing astrocytic GABA-T may be sufficient to influence the excitatory/inhibitory balance in the brain and associated behaviors. Our study implies that the therapeutic benefits of pharmacological GABA-T suppression may be largely attributed to the modulation of astrocytic GABA-T and its impact on tonic GABA release from astrocytes. This study explores how boosting a specific brain process called tonic inhibition affects memory and brain function. Tonic inhibition involves a chemical called γ-aminobutyric acid (GABA) that helps downregulate brain activity. Researchers wanted to understand how blocking GABA degradation in brain cells called astrocytes affects this process. The study focused on the hippocampus, a brain area important for memory. Researchers used mice to test their ideas. They reduced the expression of an enzyme called GABA transaminase in astrocytes, which normally helps break down GABA. This reduction increased astrocytic GABA release, enhancing tonic inhibition and reducing brain cell activity. They found that this change impaired long-term memory but not short-term memory. The results suggest that astrocytic GABA transaminase plays a crucial role in controlling brain activity and memory. By manipulating this enzyme, scientists might develop new treatments for neurological disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.