The role of calcium-permeable AMPA receptors in disynaptic feedforward inhibition in the rat prefrontal cortex

Calcium-permeable AMPA receptors (CP-AMPARs) play an important role in synaptic transmission and plasticity, but they also can induce neuronal death under certain pathological conditions. The involvement of CP-AMPARs in the pathogenesis of many diseases of the central nervous system makes them an attractive target for selective pharmacological blockade, to prevent and relieve pathological processes. However, the practical application of selective CP-AMPAR channel blockers requires a thorough study of their effects on the functioning of neural networks under the normal conditions. The goal of this study was to clarify the role of CP-AMPARs in the regulation of firing thresholds in different types of cortical neurons, as well as their involvement in maintaining the excitation/inhibition balance in the cortex. To do this, we have investigated the effects of CP-AMPARs blockade on the amplitude of excitatory postsynaptic potentials (EPSPs) and the threshold of action potentials evoked by extracellular stimulation. Whole-cell current-clamp recordings were carried out from pyramidal cells and fast-spiking interneurons in the slices of rat medial prefrontal cortex. CP-AMPARs were blocked with a selective channel blocker IEM-1460 (100 μM), the dicationic derivative of adamantane. It was found that the blockade of CP-AMPARs reduced the amplitude EPSPs in interneurons but not in pyramidal cells. In addition, it reduced the firing threshold in pyramidal cells via partial suppression of feedforward inhibition. Thus, the blockade of CP-AMPA receptors shifts the balance between cortical excitation and inhibition toward excitation.