Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks.
Cholinergic control of the activity of human cerebral cortical circuits has long been thought to be accounted for by the interaction of acetylcholine (ACh) with muscarinic receptors. Here we report the discovery of functional nicotinic receptors (nAChRs) in interneurons of the human cerebral cortex and discuss the physiological and clinical implications of these findings. The whole-cell mode of the patch-clamp technique was used to record responses triggered by U-tube application of the nonselective agonist ACh and of the alpha7-nAChR-selective agonist choline to interneurons visualized by means of infrared-assisted videomicroscopy in slices of the human cerebral cortex. Choline induced rapidly desensitizing whole-cell currents that, being sensitive to blockade by methyllycaconitine (MLA; 50 nM), were most likely subserved by an alpha7-like nAChR. In contrast, ACh evoked slowly decaying whole-cell currents that, being sensitive to blockade by dihydro-beta-erythroidine (DHbetaE; 10 microM), were most likely subserved by an alpha4beta2-like nAChR. Application of ACh (but not choline) to the slices also triggered GABAergic postsynaptic currents (PSCs). Evidence is provided that ACh-evoked PSCs are the result of activation of alpha4beta2-like nAChRs present in preterminal axon segments and/or in presynaptic terminals of interneurons. Thus, nAChRs can relay inhibitory and/or disinhibitory signals to pyramidal neurons and thereby modulate the activity of neuronal circuits in the human cerebral cortex. These mechanisms, which appear to be retained across species, can account for the involvement of nAChRs in cognitive functions and in certain neuropathological conditions.
Alkondon
M
M
Departments of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Pereira
E F
EF
Eisenberg
H M
HM
Albuquerque
E X
EX
D000109:Acetylcholine / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology* / Q000502:physiology; D002648:Child; D002794:Choline / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D007306:Insecticides / Q000494:pharmacology; D007395:Interneurons / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D016318:Quisqualic Acid / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000502:physiology*; D013268:Stimulation, Chemical; D013779:Tetrodotoxin / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology
D000109:Acetylcholine; D000157:Aconitine; D001640:Bicuculline; D002794:Choline; D004079:Dihydro-beta-Erythroidine; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D007306:Insecticides; D016318:Quisqualic Acid; D011978:Receptors, Nicotinic; D013779:Tetrodotoxin; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid; C579167:Chrna7 protein, human; C054634:methyllycaconitine