Slc9a1, which encodes the Na+/H+ exchanger isoform one (NHE1) in mammals, consists of 12 membrane domains and a cytosolic C-terminal domain. NHE1 is crucial for maintaining intracellular pH homeostasis by exchanging one intracellular proton for one extracellular sodium ion [2,3]. It is involved in various biological processes and has been associated with multiple diseases, highlighting its overall biological importance. Genetic models, such as knockout mouse models, have been valuable in studying its functions.

In conditional Slc9a1 knockout (cKO) mouse white matter tissues post-stroke, deletion of Slc9a1 in Cx3cr1+ cells led to the expansion of a microglial subgroup with elevated transcription of white matter myelination genes. This subgroup also had more acidic pHi and upregulated CREB signaling. Correspondingly, there was an enrichment of a related oligodendrocyte subgroup with pro-phagocytosis and lactate shuffling gene expression, suggesting that attenuation of NHE1-mediated H+ extrusion acidifies microglia/macrophage, stimulates CREB1 signaling, and promotes restorative microglia-oligodendrocyte interactions for remyelination [1]. Mice with a homozygous null mutation in Slc9a1 exhibited ataxia, recurrent seizures, and selective neuronal cell death, indicating its essential role in the central nervous system [2].

In summary, Slc9a1 is essential for maintaining intracellular pH balance. Through gene-knockout models, its critical role in the central nervous system, such as in preventing ataxia and seizures, and in the white matter remyelination process after stroke, has been revealed. These findings contribute to our understanding of related neurological diseases and potentially offer new perspectives for treatment strategies.