title: Lysosomal dysfunction produces distinct alterations in synaptic alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid and N-methyl-D-aspartate receptor currents in hippocampus.
abstract: The early processes that lead to synaptic dysfunction during aging are not clearly understood. Dysregulation of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors may cause age-related cognitive decline. Using hippocampal slice cultures exhibiting lysosomal dysfunction, an early marker of brain aging that is linked to protein accumulation, we identified alterations to AMPA and NMDA receptor-mediated synaptic currents. The miniature and spontaneous excitatory postsynaptic currents that were examined after 3, 6, and 9 days of lysosomal disruption showed progressive changes in amplitude, frequency, and rise and decay kinetics. To investigate whether modifications in specific channel properties of single synaptic receptors contributed to changes in the amplitude and time course of synaptic currents, we examined the single channel properties of synaptic AMPA and NMDA receptors. The channel open probability and the mean open times showed decreases in both receptor populations, whereas the closed times were increased without any change in the channel conductance. The Western blot analysis revealed a progressive decline in synaptic markers including glutamate receptor subunits. These results indicate that lysosomal dysfunction leads to progressive functional perturbation of AMPA and NMDA receptors in this slice model of protein accumulation, suggesting that age-related cognitive decline could result from altered glutamate receptor function before reductions in synaptic density.
authors.affiliation: Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kanju
authors.forename: Kodeeswaran
authors.initials: K
authors.lastname: Parameshwaran
authors.forename: Thirumalini
authors.initials: T
authors.lastname: Vaithianathan
authors.forename: Catrina M
authors.initials: CM
authors.lastname: Sims
authors.forename: Kevin
authors.initials: K
authors.lastname: Huggins
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bendiske
authors.forename: Sophia
authors.initials: S
authors.lastname: Ryzhikov
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
mesh_terms: D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D004553:Electric Conductivity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008247:Lysosomes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism