Abstract
The real-time live fluorescent monitoring of surface AMPA receptors (AMPARs) could open new opportunities for drug discovery and phenotypic screening concerning neuropsychiatric disorders. We have developed FORTIS, a tool based on pH sensitivity capable of detecting subtle changes in surface AMPARs at a neuronal population level. The expression of SEP-GluA1 or pHuji-GluA1 recombinant AMPAR subunits in mammalian neurons cultured in 96-well plates enables surface AMPARs to be monitored with a microplate reader. Thus, FORTIS can register rapid changes in surface AMPARs induced by drugs or genetic modifications without having to rely on conventional electrophysiology or imaging. By combining FORTIS with pharmacological manipulations, basal surface AMPARs, and plasticity-like changes can be monitored. We expect that employing FORTIS to screen for changes in surface AMPARs will accelerate both neuroscience research and drug discovery.
Highlights
In the central nervous system (CNS), excitatory glutamatergic synapses control neurotransmission mediated by ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
FORTIS is successful in detecting the effects of drugs on surface AMPARs
AMPARs are a target of interest for drug discovery and development as they play a critical role in synaptic plasticity mechanisms that may underlie learning and memory[16,18,84,85]
Summary
In the central nervous system (CNS), excitatory glutamatergic synapses control neurotransmission mediated by ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Regulating the exo- and endocytosis of AMPAR is a critical aspect of synaptic plasticity, influencing long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses. Approaches to monitoring synaptic transmission and synaptic plasticity have focused on both electrophysiology and the imaging of individual dendritic spines. Both methods are well established and supply considerable information regarding synaptic function in a variety of conditions. Such approaches are labor-intensive and low-throughput, and they are not suited to the fast evaluation of drugs or rapid phenotyping. The pharmacological data obtained with immortalized cells do not always reflect the compounds’
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