Implications of gamma band activity in the pedunculopontine nucleus

Abstract

The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high-frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation for the treatment of Parkinson's disease, modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high-frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder.

Keywords: Arousal; Gamma oscillations; N-type; P/Q-type; Sleep/wake.

Figure 1. Intracellular pathways and calcium channels differentially related to waking vs REM sleep

Representation of effects of acetylcholine (ACh) activation of a muscarinic 2 cholinergic receptor (M₂R) acting through G protein coupling to phospholipase C (PLC), that in turn cleaves phospholipid phosphatidylinositol biphosphate (PIP₂) into inositol triphosphate (IP3). IP3 is released and binds to IP3 receptors in the endoplasmic reticulum (ER) to release calcium (Ca²⁺). One of the intracellular pathways activated involves CaMKII, which modulates P/Q-type calcium channels and the other pathway involves cAMP/PKA, which modulates N-type calcium channels. The CaMKII/P/Q-type pathway mediates beta/gamma band activity during waking, while the cAMP/PKA/N-type pathway mediates beta/gamma band activity during REM sleep.

Figure 2. Different PPN cells modulated by N-type channels only, P/Q-type channels only, and both N- and P/Q-type channels

Top. PPN cells with only P/Q-type calcium channels (20%) are assumed to be “Wake-on” and modulated by CaMKII (left side, blue channels). PPN cells with both N- and P/Q-type calcium channels (50%) are assumed to be Wake/REM-on” and modulated by both CaMKII and cAMP/PKA metabolic pathways (middle, blue and green channels). PPN cells with only N-type calcium channels (30%) are assumed to be “REM-on’ and modulated by the cAMP/PKA pathway (right side, green channels). P/Q-only and N+P/Q cells thus are expected to be active during waking, while N-only and N+P/Q cells are active during REM sleep. Bottom. Left records (blue) show that P/Q-only cells manifested ramp-induced oscillations (first recording) that were not affected by conotoxin (CgTX) (middle recording), but were completely blocked by Aga (right recording). Middle bottom records (blue-green) show that N+P/Q cells manifested ramp-induced oscillations (left recording) that were reduced by CgTx (middle recording), and were further reduced by agatoxin (Aga) (right recording). Right records (green) show that N-only cells manifested ramp-induced oscillations (left recording) that were not affected by Aga (middle recording), but were completely blocked by CgTx (right recording). Data from Luster et al 2015.

Figure 3. Correlation between the developmental decrease in REM sleep and N-type channel expression

A) Developmental decrease in REM sleep as a percent of sleep time after Jouvet-Mounier et al (1970). In the rodent, the decrease occurs between 10 and 30 days before assuming adult levels. B) Relative quantity of N-type calcium channel (red lines) and P/Q-type calcium channel (blue lines) expression at 10 vs 30 days in punches from brain slices containing the PPN. Three replications in each of double samples showed that N-type channel expression significantly decreased >75%, while P/Q-type channel expression decreased <35%. C) Relative quantity of N-type calcium channel (red lines) and P/Q-type calcium channel (blue lines) expression at 10 vs 30 days in punches from brain slices containing the hippocampus (HIPP). N-type calcium channel (red lines) expression did not change between 10 and 30 days, while P/Q-type calcium channel (blue lines) expression increased ~50% during the same period in the HIPP. * p<0.05, ** p<0.01, NS not significant. Data from Garcia-Rill et al 2015.

Figure 4. Effects of NCS-1 on PPN neurons amplify oscillations at low concentrations (1 µM), block oscillations at high concentrations (10 µM), while lithium inhibits the effects of NCS-1 on oscillations

A) Representative 1 sec long current ramp-induced oscillations in a PPN neuron in fast synaptic blockers and tetrodotoxin in the extracellular solution and 1 µM NCS-1 in the recording pipette (left record). After 10 min of NCS-1 diffusing into the cell, the oscillatory activity increased slightly (middle record). However, after 25 min of NCS-1 diffusion both oscillation amplitude and frequency were increased (right record). B) Representative ramp-induced oscillations recorded during 1 sec long current ramps in the presence of fast synaptic blockers and tetrodotoxin and NCS-1 at 10 µM in the recording pipette (left record). After 10 min of NCS-1 diffusing into the cell, the oscillation amplitude increased slightly (middle record). However, testing at 25 min showed a decrease in amplitude compared to both 0 min and 10 min recordings (right record). C) Representation of effects of ACh activation of a M₂R acting through G protein coupling to PLC, that in turn cleaves PIP₂ into IP3. IP3 is released and binds to IP3 receptors in the ER to release calcium (Ca²⁺). One of the intracellular pathways activated involves NCS-1, which stimulates P/Q-type calcium channels and somewhat inhibits N-type calcium channels. NCS-1 at low concentrations increases gamma oscillations while NCS-1 at high concentrations blocks them. In addition, NCS-1 over expression is inhibited by 1 mM lithium (Li⁺), removing the blockade of gamma oscillations and restoring the maintenance of gamma band activity in these cells. Data from D’Onofrio et al 2015a, .