Exogenous AMPA downregulates gamma-frequency network oscillation in CA3 of rat hippocampal slices

Abstract

Pharmacologically-induced persistent hippocampal γ oscillation in area CA3 requires activation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs). However, we demonstrated that exogenous AMPA dose-dependently inhibited carbachol (CCH)-induced γ oscillation in the CA3 area of rat hippocampal slices, but the underlying mechanism is not clear. Application of AMPARs antagonist NBQX (1 μM) did not affect γ oscillation power (γ power), nor AMPA-mediated γ power reduction. At 3 μM, NBQX had no effect on γ power but largely blocked AMPA-mediated γ power reduction. Ca2+-permeable AMPA receptor (CP-AMPAR) antagonist IEM1460 or CaMKK inhibitor STO-609 but not CaMKIIα inhibitor KN93 enhanced γ power, indicating that activation of CP-AMPAR or CaMKK negatively modulated CCH-induced γ oscillation. Either CP-AMPAR antagonist or CaMKK inhibitor alone did not affected AMPA-mediated γ power reduction, but co-administration of IEM1460 and NBQX (1 μM) largely prevented AMPA-mediated downregulation of γ suggesting that CP-AMPARs and CI-AMPARs are involved in AMPA downregulation of γ oscillation. The recurrent excitation recorded at CA3 stratum pyramidale was significantly reduced by AMPA application. Our results indicate that AMPA downregulation of γ oscillation may be related to the reduced recurrent excitation within CA3 local neuronal network due to rapid CI-AMPAR and CP-AMPAR activation.

Mechanisms of Sustained Increases in γ Power Post-Ketamine in a Computational Model of the Hippocampal CA3: Implications for Ketamine’s Antidepressant Mechanism of Action

“…Following the original implementation of the CA3 model by Neymotin et al [8], our model includes both NMDA and AMPA receptors, and we upscaled the AMPA receptors to simulate the effects of ketamine. However, it should be noted that the impact of the AMPA receptors on γ oscillations is not necessarily straightforward [53], and our model is naturally very simplified. For example, the study conducted by Li et al [53] demonstrated that the application of the synthetic glutamate analog AMPA to CA3 slices ex vivo led to the downregulation of γ oscillation power, but it increased the peak oscillation frequency, and they linked this effect to the modulation of an intracellular signaling pathway impacting neuronal excitability [53].…”

“…However, it should be noted that the impact of the AMPA receptors on γ oscillations is not necessarily straightforward [53], and our model is naturally very simplified. For example, the study conducted by Li et al [53] demonstrated that the application of the synthetic glutamate analog AMPA to CA3 slices ex vivo led to the downregulation of γ oscillation power, but it increased the peak oscillation frequency, and they linked this effect to the modulation of an intracellular signaling pathway impacting neuronal excitability [53]. Although this study highlights that AMPAR activation will not necessarily lead to γ power upregulation in all cases, it should be noted that AMPA is not found endogenously to begin with.…”