AMPAkines are positive modulators of
AMPA receptors, and previous work has shown that these compounds can facilitate synaptic plasticity and improve learning and memory in both animals and humans; thus, their role in the treatment of
cognitive impairment is worthy of investigation. In this study, we have utilized an organotypic slice model in which
chloroquine-induced lysosomal dysfunction produces many of the pathogenic attributes of
Alzheimer's disease. Our previous work demonstrated that synaptic
AMPA receptor function is impaired in hippocampal slice cultures exhibiting lysosomal dysfunction leading to
protein accumulation. The present study investigated the effect of the AMPAkine
CX516 on AMPAR-mediated synaptic transmission as well as the
CX516 induced modification of single channel
AMPA receptor properties in this organotypic slice-culture model. In whole cell recordings from CA1 pyramidal neurons in
chloroquine-treated slices we observed a significant decrease in AMPAR-mediated mEPSC frequency and amplitude indicating synaptic dysfunction. Following application of
CX516, these parameters returned to nearly normal levels. Similarly, we report
chloroquine-induced impairment of AMPAR single channel properties (decreased probability of opening and mean open time), and significant recovery of these properties following
CX516 administration. These results suggest that
AMPA receptors may be potential
pharmaceutical targets for the treatment of
neurodegenerative diseases, and highlights AMPAkines, in particular, as possible therapeutic agents.