| First Author | Gao AYL | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 130 |
| Pages | 104490 | PubMed ID | 31175985 |
| Mgi Jnum | J:326509 | Mgi Id | MGI:6381823 |
| Doi | 10.1016/j.nbd.2019.104490 | Citation | Gao AYL, et al. (2019) A Christianson syndrome-linked deletion mutation (Delta287ES288) in SLC9A6 impairs hippocampal neuronal plasticity. Neurobiol Dis 130:104490 |
| abstractText | Christianson Syndrome is a rare but increasingly diagnosed X-linked intellectual disability disorder that arises from mutations in SLC9A6/NHE6, a pH-regulating transporter that localizes to early and recycling endosomes. We have recently reported that one of the originally identified disease-causing mutations in NHE6 (p.E287-S288del, or DeltaES) resulted in a loss of its pH regulatory function. However, the impact of this mutation upon neuronal synapse formation and plasticity is unknown. Here, we investigate the consequences of the DeltaES mutant upon mouse hippocampal pyramidal neurons by expressing a fluorescently-labeled DeltaES NHE6 construct into primary hippocampal neurons. Neurons expressing the DeltaES mutant showed significant reductions in mature dendritic spine density with a concurrent increase in immature filopodia. Furthermore, compared to wild-type (WT), DeltaES-containing endosomes are redirected away from early and recycling endosomes toward lysosomes. In parallel, the DeltaES mutant reduced the trafficking of glutamatergic AMPA receptors to excitatory synapses and increased their accumulation within lysosomes for potential degradation. Upon long-term potentiation (LTP), neurons expressing DeltaES failed to undergo significant structural and functional changes as observed in controls and WT transfectants. Interestingly, synapse density and LTP-induced synaptic remodeling in DeltaES-expressing neurons were partially restored by bafilomycin, a vesicular alkalinisation agent, or by leupeptin, an inhibitor of lysosomal proteolytic degradation. Overall, our results demonstrate that the ES mutation attenuates synapse density and structural and functional plasticity in hippocampal neurons. These deficits may be partially due to the mistargeting of AMPA receptors and other cargos to lysosomes, thereby preventing their trafficking during synaptic remodeling. This mechanism may contribute to the cognitive learning deficits observed in patients with Christianson Syndrome and suggests a potential therapeutic strategy for treatment. |
