title: α4β2∗nicotinic receptors stimulate GABA release onto fast-spiking cells in layer V of mouse prefrontal (Fr2) cortex.
abstract: Nicotinic acetylcholine receptors (nAChRs) produce widespread and complex effects on neocortex excitability. We studied how heteromeric nAChRs regulate inhibitory post-synaptic currents (IPSCs), in fast-spiking (FS) layer V neurons of the mouse frontal area 2 (Fr2). In the presence of blockers of ionotropic glutamate receptors, tonic application of 10μM nicotine augmented the spontaneous IPSC frequency, with minor alterations of amplitudes and kinetics. These effects were studied since the 3rd postnatal week, and persisted throughout the first two months of postnatal life. The action of nicotine was blocked by 1μM dihydro-β-erythroidine (DHβE; specific for α4∗nAChRs), but not 10nM methyllycaconitine (MLA; specific for α7∗nAChRs). It was mimicked by 10nM 5-iodo-3-[2(S)-azetidinylmethoxy]pyridine (5-IA; which activates β2∗nAChRs). Similar results were obtained on miniature IPSCs (mIPSCs). Moreover, during the first five postnatal weeks, approximately 50% of FS cells displayed DHβE-sensitive whole-cell nicotinic currents. This percentage decreased to ∼5% in mice older than P45. By confocal microscopy, the α4 nAChR subunit was immunocytochemically identified on interneurons expressing either parvalbumin (PV), which mainly labels FS cells, or somatostatin (SOM), which labels the other major interneuron population in layer V. GABAergic terminals expressing α4 were observed to be juxtaposed to PV-positive (PV+) cells. A fraction of these terminals displayed PV immunoreactivity. We conclude that α4β2∗nAChRs can produce sustained regulation of FS cells in Fr2 layer V. The effect presents a presynaptic component, whereas the somatic regulation decreases with age. These mechanisms may contribute to the nAChR-dependent stimulation of excitability during cognitive tasks as well as to the hyperexcitability caused by hyperfunctional heteromeric nAChRs in sleep-related epilepsy.
authors: Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, piazza della Scienza 2, Milano 20126, Italy.
authors: Patrizia
authors: P
authors: Aracri
authors: Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, piazza della Scienza 2, Milano 20126, Italy.
authors: Simone
authors: S
authors: Meneghini
authors: Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, piazza della Scienza 2, Milano 20126, Italy.
authors: Aurora
authors: A
authors: Coatti
authors: Department of Biosciences, University of Milano, Via Celoria 26, Milano 20133, Italy.
authors: Alida
authors: A
authors: Amadeo
authors: Department of Biotechnology and Biosciences, and NeuroMI (Milan Center of Neuroscience), University of Milano-Bicocca, piazza della Scienza 2, Milano 20126, Italy. Electronic address: andrea.becchetti@unimib.it.
authors: Andrea
authors: A
authors: Becchetti
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D005260:Female; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents; D010320:Parvalbumins; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid
keywords: IPSC; PFC; heteromeric nAChR; interneuron; parvalbumin; somatostatin