a4b2* Nicotinic Receptors Stimulate Gaba Release onto Fast-Spiking Cells in Layer V of Mouse Prefrontal (Fr2) Cortex

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 10 mu M 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 1 mu M dihydro-beta-erythroidine (DH beta E; specific for alpha 4* nAChRs), but not 10 nM methyllycaconitine (MLA; specific for alpha 7* nAChRs). It was mimicked by 10 nM 5-iodo-3-[2(S)-azetidinyl methoxy]pyridine (5-IA; which activates beta 2* nAChRs). Similar results were obtained on miniature IPSCs (mIPSCs). Moreover, during the first five postnatal weeks, approximately 50% of FS cells displayed DHI3E-sensitive whole cell nicotinic currents. This percentage decreased to similar to 5% in mice older than P45. By confocal microscopy, the alpha 4 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 alpha 4 were observed to be juxtaposed to PV-positive (PV+) cells. A fraction of these terminals displayed PV immunoreactivity. We conclude that alpha 4 beta 2* 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.