Restoring hippocampal sharp-wave ripples under glutamate transporter dysfunction

Abstract

Disruption of glutamate homeostasis is believed to contribute to the early progression of Alzheimers disease (AD) and associated neurodegeneration. Soluble amyloid-{beta} oligomers impair excitatory amino acid transporters (EAATs), reducing glutamate clearance, while also enhancing glutamate release from neurons and astrocytes. Together, these effects produce persistent glutamatergic dysregulation that disrupts synaptic and network function. Here, we asked whether the effects of EAAT attenuation can be mitigated through ion-channel modulation. TBOA, a selective EAAT inhibitor, was used to model early-stage glutamatergic dysregulation. TBOA reduced the local field potential amplitude of hippocampal sharp-wave ripples (SWRs) in mouse hippocampal slices, suggesting that glutamate accumulation disrupts network synchrony. Calcium imaging further showed that TBOA diminished SWR-associated population calcium transients while promoting spontaneous calcium transients in individual neurons, indicating a shift from coordinated population activity toward disorganized cellular activity. KCNQ-channel openers ML213 and ICA-27243 partially restored the TBOA-induced decline in SWR amplitude. In contrast, similar restorative effects were not observed following modulation of other ion channels, including blockade of AMPA and NMDA receptors or HCN/Ih channels, or activation of large-conductance Ca2+-activated K+ (BK) channels and G-protein-activated inwardly rectifying potassium (GIRK) channels. Together, these findings suggest that KCNQ-channel openers may occupy a unique position in mitigating glutamate-related hyperexcitability during early AD-associated network dysfunction.