ALDH2-mediated GABA biosynthesis regulates hippocampal LTP and learning adaptability

Hippocampal plasticity has an undisputed role in learning and memory. Despite decades of research focusing on the neurobiological basis of synaptic plasticity, relatively little is known about the metabolic dynamics leading to hippocampal plasticity at the single-cell level. Here we used single-cell mass spectrometry to dissect metabolomic changes of excitatory pyramidal neurons (PNs), inhibitory interneurons and astrocytes in hippocampus during long-term potentiation (LTP) and learning-related behaviors in mice. We identified an enhancement of the γ-aminobutyric acid (GABA) biosynthetic pathway in CA1 PNs during LTP. This LTP-sensitive GABA metabolic pathway was mediated through an aldehyde dehydrogenase 2 (ALDH2)-dependent mechanism. Selective deletion of PN ALDH2 blocked the LTP-related GABA enhancement and impaired learning adaptability. Thus, profiling of the single-cell metabolome is established to characterize an activity-dependent GABA pathway and its impact on hippocampal plasticity and learning. This GABA signaling pathway identified in glutamatergic neurons represents a novel target for learning and memory.