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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00899

DOI=10.3389/fphar.2017.00899

ISSN=1663-9812

ABSTRACT=<p>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 A<sub>1</sub> adenosine receptors (A<sub>1</sub>R), neither the role of A<sub>1</sub>R 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 A<sub>1</sub>R-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 A<sub>1</sub>R. Indeed, the A<sub>1</sub>R-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 <italic>versus</italic> extra-synaptic human cortical A<sub>1</sub>R, probably resulting from a different molecular organization of A<sub>1</sub>R 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.</p>