Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area

Abstract

Neuronal synchronization at gamma band frequency (20–80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 μM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 μM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Modulation of Hippocampal Gamma Oscillations by Dopamine in Heterozygous Reeler Mice in vitro

“…PI3K is one of the downstream molecules in NMDAR activation, in which calcium influx through the NR2B subunit of NMDAR leads to the activation of PI3K (Brennan-Minnella et al, 2013). A previous study shows that nicotinic modulation of hippocampal γ oscillations involves PI3K activation (Wang et al, 2017). These studies indicate that PI3K may be involved in the modulation of γ oscillations in HRM.…”

“…Previous studies indicate that reelin acts on its receptor and activates the PI3K-Akt-mammalian target of rapamycin (mTOR) pathway (Hwa and Gabriella, 2016). Therefore, we examined the effect of wortmannin, a potent and selective inhibitor of PI3K, at a physiological dose (Wang et al, 2017) on γ oscillations of rat hippocampal slices from WTM and HRM. When wortmannin was applied to hippocampal slices, γ power was significantly increased by 39 ± 12% in WTM (CCh + Wort, 973.39 ± 252.78 µV 2 vs. CCh, 715.89 ± 175.34 µV 2 , F (2,9) = 9.908, P = 0.001, RM ANOVA, Figures 4A,B,E), and a further application of DA (20 µM) caused an additional 23 ± 7% increase in γ power, but such an increase did not reach statistical significance compared with that in wortmannin (1,150.03 ± 273.81 µV 2 vs. CCh + Wort, T = 1.801, P = 0.09, RM ANOVA, followed by the Holm-Sidak method, Figures 4A,B,E).…”

Single-fluorophore biosensors for sensitive and multiplexed detection of signalling activities

“…Subtle shifts in kinase activity are often critical for finely tuning the behavior of important physiological processes, such as the modulation of synaptic plasticity 27,28 , neuronal activity oscillations 29 , cardiac myofibril contraction 30 , and mechano-sensitive signaling 31 by PKA. While these minute changes in kinase activity often approach the detection limit of genetically encoded FRET-based biosensors 32 , our results suggest that such physiologically relevant, subtle changes in kinase activity may be readily detectable using ExRai-KARs.…”

Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission

“…It is well known that expression and transcriptional activity of PPAR␥ is affected by the cross talk with several kinases, phosphatases (i.e., ERK-and p38-MAPK, PKA, PKC GSK3; Rochette-Egly, 2003) and cAMP response element binding protein (CREB; Liu et al, 2016). All these intracellular signaling elements are also known for their role in mediating nicotine effects (Brunzell et al, 2003;Burns and Vanden Heuvel, 2007;Michalak and Biala, 2017;Wang et al, 2017). Notably, Fisher et al (2017) highlighted distinct roles of CREB within the HIPP in mediating nicotine withdrawal phenotypes in animals chronically treated with nicotine and undergoing 24 h into the withdrawal phase.…”

“…Initially, PPAR␥ expression in the brain was suggested mainly in astrocytes, and glial cells (Sarruf et al, 2009). Recent studies, however, suggest that PPAR␥ expression in the brain occurs almost exclusively in neurons and astrocytes (Warden et al, 2016). PPAR␥ agonists have been shown to modulate genes linked to synaptic transmission and neuronal function in regions such as the amygdala (AMY) and hippocampus (HIPP; Searcy et al, 2012;Ferguson et al, 2014).…”