Caffeine Controls Glutamatergic Synaptic Transmission and Pyramidal Neuron Excitability in Human Neocortex.

Amber Kerkhofs,Johannes C Baayen,Ana C Xavier,Sander Idema,Paula M Canas,Samira G Ferreira,Beatriz S Da Silva,Huibert D Mansvelder,Rodrigo A Cunha

doi:10.3389/fphar.2017.00899

Abstract

Caffeine is the most widely used psychoactive drug, bolstering attention and normalizing mood and cognition, all functions involving cerebral cortical circuits. Whereas studies in rodents showed that caffeine acts through the antagonism of inhibitory A1 adenosine receptors (A1R), neither the role of A1R nor the impact of caffeine on human cortical neurons is known. We here provide the first characterization of the impact of realistic concentrations of caffeine experienced by moderate coffee drinkers (50 μM) on excitability of pyramidal neurons and excitatory synaptic transmission in the human temporal cortex. Moderate concentrations of caffeine disinhibited several of the inhibitory A1R-mediated effects of adenosine, similar to previous observations in the rodent brain. Thus, caffeine restored the adenosine-induced decrease of both intrinsic membrane excitability and excitatory synaptic transmission in the human pyramidal neurons through antagonism of post-synaptic A1R. Indeed, the A1R-mediated effects of endogenous adenosine were more efficient to inhibit synaptic transmission than neuronal excitability. This was associated with a distinct affinity of caffeine for synaptic versus extra-synaptic human cortical A1R, probably resulting from a different molecular organization of A1R in human cortical synapses. These findings constitute the first neurophysiological description of the impact of caffeine on pyramidal neuron excitability and excitatory synaptic transmission in the human temporal cortex, providing adequate ground for the effects of caffeine on cognition in humans.

Highlights

Coffee is the second most consumed beverage after water and its main constituent, caffeine, is the most widely consumed drug, improving attention and alertness, and normalizing mood and cognition (Fredholm et al, 1999; Smith, 2002)
We provide the first characterization of the impact of caffeine concentrations experienced by moderate coffee drinkers (50 μM) on neuronal excitability in pyramidal neurons and excitatory synapses of the human temporal cortex
Caffeine had a larger affinity for synaptic A1 receptors (A1R) compared to extra-synaptic A1R in the human temporal cortex, which contrasts with the affinity profile of caffeine in the rodent cortex; this difference probably results from a different molecular organization of A1R within human cortical synapses compared to rodent cortical synapses

Summary

Introduction

Coffee is the second most consumed beverage after water and its main constituent, caffeine, is the most widely consumed drug, improving attention and alertness, and normalizing mood and cognition (Fredholm et al, 1999; Smith, 2002). A1R depress synaptic transmission and neuronal excitability through a combined presynaptic action decreasing glutamate release, post-synaptic actions decreasing the activation of glutamate receptors and voltage-sensitive calcium channels (de Mendonça et al, 1995; Klishin et al, 1995) as well as extra-synaptic actions through a decrease of neuronal excitability by controlling potassium rectifier channels (Greene et al, 1985), after-hyperpolarization potentials (Haas and Greene, 1984) and HCN (Li et al, 2011) Both in vivo and in vitro studies in rodents concluded that the inhibitory effect of A1R predominantly results from the presynaptic inhibition of glutamate release (Phillis et al, 1979; Thompson et al, 1992)

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