title: Integration of inhibitory and excitatory effects of α7 nicotinic acetylcholine receptor activation in the prelimbic cortex regulates network activity and plasticity.
abstract: Cognitive and attentional processes governed by the prefrontal cortex (PFC) are influenced by cholinergic innervation. Here we have explored the role of α7 nicotinic acetylcholine receptors (nAChRs) as mediators of cholinergic signalling in the dorsomedial (prelimbic) PFC, using mouse brain slice electrophysiology. Activation of α7 nAChRs located on glutamatergic terminals and cell soma of GABAergic interneurons increased excitation and inhibition, respectively, in layer V of the prelimbic cortex. These actions were distinguished by their differential dependence on local acetylcholine (ACh): potentiation of endogenous cholinergic signalling with the positive allosteric modulator, PNU-120596, enhanced spontaneous excitatory events, an effect that was further increased by inhibition of acetylcholinesterase. In contrast, α7 nicotinic modulation of inhibitory signalling required addition of exogenous agonist (PNU-282987) as well as PNU-120596, and was unaffected by acetylcholinesterase inhibition. Thus α7 nAChRs can bi-directionally regulate network activity in the prelimbic cortex, depending on the magnitude and localisation of cholinergic signalling. This bidirectional influence is manifest in dual effects of α7 nAChRs on theta-burst-induced long-term potentiation (LTP) in layer V of the prelimbic cortex. Antagonism of α7 nAChRs significantly decreased LTP implicating a contribution from endogenous ACh, consistent with the ability of local ACh to enhance glutamatergic signalling. Exogenous agonist plus potentiator also decreased LTP, indicative of the influence of this drug combination on inhibitory signalling. Thus α7 nAChRs make a complex contribution to network activity and synaptic plasticity in the prelimbic cortex.
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Udakis
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors.forename: Victoria Louise
authors.initials: VL
authors.lastname: Wright
authors.affiliation: Department of Biology & Biochemistry, University of Bath, Bath BA2 7AY, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Wonnacott
authors.affiliation: Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK. Electronic address: C.P.Bailey@bath.ac.uk.
authors.forename: Christopher Philip
authors.initials: CP
authors.lastname: Bailey
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D007555:Isoxazoles; C498513:PNU-282987; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000110:Acetylcholinesterase; D000109:Acetylcholine
keywords: GABA; Glutamate; LTP; Nicotinic receptors; Prefrontal cortex; Prelimbic cortex