Cerebral Cortex Advance Access originally published online on September 30, 2004
Cerebral Cortex 2005 15(7):921-928; doi:10.1093/cercor/bhh191
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Cerebral Cortex V 15 N 7 © Oxford University Press 2004; all rights reserved
Nootropic Agents Enhance the Recruitment of Fast GABAA Inhibition in Rat Neocortex
1 Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA and 2 Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA
Address correspondence to Douglas S.F. Ling, Department of Physiology and Pharmacology, SUNY Downstate Medical School, 450 Clarkson Ave., Box 29, Brooklyn, NY 11203, USA. Email: dling{at}downstate.edu.
It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of 
-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation–inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABAA receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.
Key Words: aniracetam • cortex • cyclothiazide • EPSC • IPSC • synaptic inhibition
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