Abstract
GABAergic inhibition plays a critical role in the regulation of neuron excitability; thus, it is subject to modulations by many factors. Recent evidence suggests the elevation of intracellular calcium ([Ca2+]i) and calcium-dependent signaling molecules underlie the modulations. Caffeine induces a release of calcium from intracellular stores. We tested whether caffeine modulated GABAergic transmission by increasing [Ca2+]i. A brief local puff-application of caffeine to hippocampal CA1 pyramidal cells transiently suppressed GABAergic inhibitory postsynaptic currents (IPSCs) by 73.2 ± 6.98%. Time course of suppression and the subsequent recovery of IPSCs resembled DSI (depolarization-induced suppression of inhibition), mediated by endogenous cannabinoids that require a [Ca2+]i rise. However, unlike DSI, caffeine-induced suppression of IPSCs (CSI) persisted in the absence of a [Ca2+]i rise. Intracellular applications of BAPTA and ryanodine (which blocks caffeine-induced calcium release from intracellular stores) failed to prevent the generation of CSI. Surprisingly, ruthenium red, an inhibitor of multiple calcium permeable/release channels including those of stores, induced metaplasticity by amplifying the magnitude of CSI independently of calcium. This metaplasticity was accompanied with the generation of a large inward current. Although ionic basis of this inward current is undetermined, the present result demonstrates that caffeine has a robust Ca2+-independent inhibitory action on GABAergic inhibition and causes metaplasticity by opening plasma membrane channels.
Highlights
Caffeine is a methylxanthine that acts as a nonspecific phosphodiesterase inhibitor [1]
The concentration of caffeine that is required to initiate a calcium release is one order higher [6] than the concentration of caffeine acting on adenosine receptors and glycine receptors [7, 8], cafffeine was reported to reduce GABAergic inhibition by initiating a release of calcium from stores and activating calcium-dependent phosphatases that dephosphorylate the GABAA receptor [9]
The recovery of inhibitory postsynaptic currents (IPSCs) was immediate upon the termination of caffeine application, suggesting that caffeine directly interacted with GABAergic synapses without involving a series of intermediary molecules (Figure 1(a) right trace)
Summary
Caffeine is a methylxanthine that acts as a nonspecific phosphodiesterase inhibitor [1] It is widely used as a psychoactive stimulant [2] because it has the ability to interact with neurotransmission and induces a release of excitatory neurotransmitters while blocking adenosine receptors [3]. Caffeine is a structural analogue of strychnine [4] It competitively binds and antagonizes the glycine receptor. The concentration of caffeine that is required to initiate a calcium release is one order higher (which is in a mM range) [6] than the concentration of caffeine acting on adenosine receptors and glycine receptors (which is in a μM range) [7, 8], cafffeine was reported to reduce GABAergic inhibition by initiating a release of calcium from stores and activating calcium-dependent phosphatases that dephosphorylate the GABAA receptor [9]. Since the eCBmediated GABAergic plasticity involves a calcium release from stores [12, 13], we examined whether caffeine modulated
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