Nicotine Enhances Firing Activity of Layer 5 Pyramidal Neurons in the Medial Prefrontal Cortex through Inhibition of Kv7 Channels

Abstract

Nicotine enhances attention, working memory and recognition. One of the brain regions associated with these effects of nicotine is the medial prefrontal cortex (mPFC). However, cellular mechanisms that induce the enhancing effects of nicotine remain unclear. To address this issue, we performed whole-cell patch-clamp recordings from mPFC layer 5 pyramidal neurons in slices of C57BL/6J mice. Shortly (approx. 2 min) after bath application of nicotine, the number of action potentials, which were elicited by depolarizing current injection, was increased, and this increase persisted for over 5 min. The effect of nicotine was blocked by the α4β2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine, α7 nAChR antagonist methyllycaconitine, or intracellular perfusion with the Ca 2 chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Additionally, the voltage-dependent potassium 7 (Kv7) channel blocker, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991), as well as nicotine, shortened the spike threshold latency and increased the spike numbers. By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4β2 and α7 nAChRs and subsequent increase in intracellular Ca 2 levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition.

Nicotine Enhances Object Recognition Memory <i>via</i> Stimulating α4β2 and α7 Nicotinic Acetylcholine Receptors in the Medial Prefrontal Cortex of Mice

“…A previous study demonstrated that nicotine stimulation results in the inhibition of layer 2/3 pyramidal neurons while layer 5 pyramidal neurons are activated by nAChR stimulation due to the specific expression pattern of nAChRs in the mPFC. 48) Additionally, our recent electrophysiological study revealed that nicotine increases firing activity of layer 5 pyramidal neurons by stimulating α4β2 and α7 nAChRs. 49) Given that the interaction of mPFC layer 5, but not layer 2/3, pyramidal neurons with the perirhinal cortex and hippocampus has been considered critical for object recognition memory acquisition and/or consolidation, 50) it is most likely that nicotine-induced activation of mPFC layer 5 pyramidal neurons may be involved in the enhanced object recognition memory observed in the present study.…”

“…Because we have recently revealed that nicotine-induced increase in firing activity of mPFC layer 5 pyramidal neurons is also blocked by either an α4β2 or an α7 nAChR antagonist, 49) it is possible that simultaneous activation of intracellular signaling mediated by these nAChR stimulation might be necessary for the increased activity of mPFC layer 5 pyramidal neurons, and thus, for enhanced object recognition memory. Alternatively, since α4β2 and α7 nAChRs have been known to regulate the release of different neurotransmitters, such as dopamine, glutamate, and noradrenaline, 12,17,48,51,52) simultaneous and complementary modulation of neurotransmitter release might be required to the effect of nicotine. In either case, further studies are necessary to address this issue.…”

Noradrenergic stimulation of α1 adrenoceptors in the medial prefrontal cortex mediates acute stress-induced facilitation of seizures in mice

“…Procedures for preparing mPFC slices and electrophysiological recordings were similar to our previous studies 26 , 33 , 34 . Mice were anesthetized with isoflurane and decapitated.…”

“…Histochemical examinations of recorded neurons were implemented as described previously 26 , 33 , 34 . After the recordings, the slices were fixed overnight in 4% paraformaldehyde in 0.1 M PBS (pH 7.4) at 4 °C.…”