Altered hippocampal sharp-wave ripples play a role in impaired memory consolidation in Christianson syndrome mouse model

In many neurological disorders, sleep disturbances and intellectual disability are strongly associated.Therefore, by studying these types of disorders, we can attempt to elucidate molecular and cellularmechanisms with broad relevance to brain function and disease. Christianson syndrome (CS) is anexample of a monogenic condition involving X-linked intellectual disability and sleep disturbances.The lack of treatment options for these children is directly related to our poor understanding of themechanisms underlying the disease. CS arises from mutations in the SLC9A6 gene which encodes theendosomal pH regulator (Na+, K+)/H+ exchanger isoform 6 (NHE6). NHE6 regulates the pH ofintracellular membrane vesicles to facilitate cargo trafficking needed for proper function anddevelopment of neurons. However, the relation between loss of NHE6, sleep disturbance and cognitivedeficits is currently unclear. In the brain, the hippocampus is the region identified in long-term memoryformation. It contains specific neurons, “place cells,” that code for the animal’s position in itsenvironment. During sleep, the hippocampus replays previously formed patterns of place cell activityassociated with population bursts orchestrated by “sharp-wave ripples” (SWRs), which are necessaryfor the consolidation of memories. In a CS murine model, we found impaired spatial cognition whilehippocampal place cells are mostly unaffected. However, SWRs are more frequent but of loweroscillatory frequency and power in CS. Our results provide novel insights into understanding impairedcognition during sleep in CS to contribute to a further understanding of the disease and contribute tofuture therapeutic interventions.