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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.
Highlights
In the neocortex, acetylcholine (ACh) regulates arousal and executive functions (Jones, 2008), and the implication of Nicotinic acetylcholine receptors (nAChRs) is increasingly recognized (Wallace and Bertrand, 2013)
The kinetic and pharmacological features of heteromeric nAChRs make them fit to regulate overall excitability, on a relatively slow time scale, as is likely to occur during non-synaptic, diffuse transmission (Lendvai and Vizi, 2008)
Functional heteromeric nAChRs are observed in GABAergic interneurons dissociated from surgical samples from human neocortex (Alkondon et al, 2000)
Summary
Acetylcholine (ACh) regulates arousal and executive functions (Jones, 2008), and the implication of nAChRs is increasingly recognized (Wallace and Bertrand, 2013). The kinetic and pharmacological features of heteromeric nAChRs make them fit to regulate overall excitability, on a relatively slow time scale, as is likely to occur during non-synaptic, diffuse transmission (Lendvai and Vizi, 2008) This concept agrees with the observation that mutant a4 and b2 subunits are frequently linked to ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy, Becchetti et al, 2015). The effect was studied since the third postnatal week, a phase of neocortex maturation and modification of nAChR expression, and was maintained at least until the end of the second postnatal month, when the neocortical circuits have reached maturity and the nAChR expression is stable (Molas and Dierssen, 2014) These results reveal a supplementary mechanism to stimulate physiological excitability as well as a possible cause of pathological hyperexcitability in prefrontal regions
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