Excitation of rat hippocampal interneurons via modulation of endogenous agonist activity at the alpha7 nicotinic ACh receptor.
The alpha7 subtype of the nicotinic acetylcholine receptor (alpha7 nAChR) is prominently expressed in the hippocampus where it is thought to play a role in the regulation of cognitive function. In this study, we have investigated the effects of 5-hydroxyindole (5-HI), a positive modulator of the alpha7 nAChR, on GABAergic activity in hippocampal CA1 stratum radiatum interneurons in acute rat brain slices. Superfusion of 5-HI (100 microM) increased the mean frequency and amplitude of spontaneous IPSCs (sIPSCs). The potentiation was occluded by pretreatment of slices with: (1) a high concentration of the broad-spectrum agonist nicotine to desensitize the alpha7 receptor, (2) an alpha7 nAChR antagonist, and (3) tetrodotoxin to block action potential firing. These results indicate that facilitation by 5-HI was mediated by the alpha7 nAChR and required neuronal excitation. In contrast, 5-HI had no effect on sIPSCs recorded in hippocampal slices from younger animals, even though the expression of functional alpha7 nAChRs was confirmed by agonist application experiments. In these slices, 5-HI only enhanced sIPSCs after pretreatment with the acetylcholinesterase inhibitor Bw284c51. Taken together, our results suggest that 5-HI facilitates GABAergic transmission via excitation of the alpha7 nAChR, and that this effect requires the presence of the endogenous agonist ACh in the extracellular environment of the receptor.
Mok
M H Selina
MH
Schizophrenia and Bipolar Neurophysiology and Pharmacology, Psychiatry CEDD, GlaxoSmithKline, Harlow, Essex CM19 5AW, UK. selina.m.mok@gsk.com
Kew
James N C
JN
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000008:administration & dosage*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000008:administration & dosage; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C579165:Chrna7 protein, rat; D007211:Indoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C026785:5-hydroxyindole; D005680:gamma-Aminobutyric Acid