AMPA Receptor Function at Interneuron Synapses

AMPA receptors (AMPARs) mediate the majority of excitatory glutamatergic synaptic transmission in the brain. Most AMPARs are impermeable to Ca2+ whereas receptors that lack the GluR2 subunit allow Ca2+ flux. Ca2+- permeable (CP) AMPARs are highly expressed in GABAergic interneurons where they contribute to synaptic plasticity that allows the brain to constantly adjust to changing conditions. A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common Ca2+-impermeable (CI) AMPARs . Inward rectification of CP-AMPARs results from intracellular polyamines that act as open channel blockers to prevent outward current flux at positive membrane potentials. Thus, rectification and sensitivity to antagonists that bind at the polyamine site provide biophysical signatures of AMPAR subunit composition and hence Ca2+ permeability. These properties have been widely used to establish rules of postsynaptic AMPAR localization, especially at interneuron synapses where AMPAR subunit-switching is a widely recognized mechanism of synaptic plasticity. However, our preliminary data suggest that CP-AMPAR rectification and pharmacology are sensitive to presynaptic factors that potentially complicate the use of these biophysical properties as sole proxies of postsynaptic subunit composition. We hypothesize that presynaptic mechanisms contribute to AMPAR biophysical properties at mossy fiber to interneuron synapses in the hippocampus, where a continuum of rectifying and non-rectifying AMPARs are expressed with established rules for plasticity based on rectification and pharmacology. We will test this idea by recording from interneuron subtypes with high CP-AMPAR content and use selective optogenetic activation of mossy fibers to minimize confounding variability of synapse specificity. Using slice electrophysiology and high-resolution Ca2+ imaging, we will determine the contribution of presynaptic properties to AMPAR biophysical properties. AMPAR subunit composition has important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology. Successful completion of the proposed studies will reveal novel properties of AMPARs that are essential for understanding their function within synapses and intact circuits. Project Number: 1R21NS147535-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jacques Wadiche | Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM, BIRMINGHAM, AL | Award Amount: $186,250 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BN-F (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11318267