Our studies provide first insights towards establishing a neurobiological role of NHE9 in a wide range of disorders including ASD and ADHD. Whole brain analysis of developing murine brain reveals highly specific and regulated expression of NHE9, consistent with a role in modulation of developing synapses in both neurons and astrocytes. Further, a previous study in rat models of ADHD suggested that SLC9A9 expression is proportional to the number of synapses based a significant correlation in the expression of SLC9A9 and the synaptophysin (SYP) genes30. Although overlapping distribution of the closely related NHE6 ortholog could result in functional redundancy, we did observe acidification of TfnR-positive endosomes upon NHE9 knockdown in human glioma cells and conversely, alkalinization resulting from enhanced expression in mouse astrocytes. Thus, NHE9 functions as H+ leak pathway in endosomes, acting as a brake against excessive luminal acidification. The luminal pH of sorting endosomes is critical in determining the direction of the cargo and plays a crucial role in receptor desensitization, degradation and cell surface delivery of receptors upon ligand dissociation53. Early and recycling endosomes have more alkaline
