Pedunculopontine arousal system physiology-Implications for schizophrenia

Abstract

Schizophrenia is characterized by major sleep/wake disturbances including increased vigilance and arousal, decreased slow wave sleep, and increased REM sleep drive. Other arousal-related symptoms include sensory gating deficits as exemplified by decreased habituation of the blink reflex. There is also dysregulation of gamma band activity, suggestive of disturbances in a host of arousal-related mechanisms. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of the disease. Recent discoveries on the physiology of the pedunculopontine nucleus help explain many of these disorders of arousal in, and point to novel therapeutic avenues for, schizophrenia.

Keywords: CaMKII, calcium/calmodulin-dependent protein kinase; Calcium channels; EEG, electroencephalogram; EPSC, excitatory postsynaptic potential; GABA, γ aminobutyric acid; Gamma band activity; InsP, inositol 1,4,5-triphosphate receptor protein; KA, kainic acid; NCS-1, neuronal calcium sensor protein 1; NMDA, n methyl d aspartic acid; Neuronal calcium sensor protein; P50 potential; PGO, ponto-geniculo-occipital; PPN, pedunculopontine nucleus; Pf, parafascicular nucleus; RAS, reticular activating system; REM, rapid eye movement; SWS, slow wave sleep; SubCD, subcoeruleus dorsalis; cAMP, cyclic adenosine monophosphate; ω-Aga, ω-agatoxin-IVA; ω-CgTx, ω-conotoxin-GVIA.

Fig. 1

Effects of NCS-1 on gamma oscillations in PPN neurons. (A) Representative 1 s 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, light gray). After 10 min of NCS-1 diffusing into the cell, the oscillatory activity increased slightly (middle record, dark gray). However, after 25 min of NCS-1 diffusion both oscillation amplitude and frequency were increased (right record, black). (B) Power spectrum of the records shown in (A) showing the increased amplitude and frequency of oscillations after 25 min exposure to 1 μM NCS-1. (C) Representative ramp-induced oscillations recorded during 1 s long current ramps in the presence of fast synaptic blockers and tetrodotoxin and NCS-1 at 10 μM in the recording pipette (left record, light gray). After 10 min of NCS-1 diffusing into the cell, the oscillation amplitude increased slightly (middle record, dark gray). However, testing at 25 min showed a decrease in amplitude compared to both 0 min and 10 min recordings (right record, black). (D) Power spectrum of the records shown in (C) demonstrating the slight increase in amplitude at 10 min, and the subsequent decrease at 25 min.

Fig. 2

Intracellular pathways mediating NCS-1 modulation of intracellular calcium and P/Q-type calcium channels. 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 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 lithium (Li⁺), removing the blockade of gamma oscillations and restoring the maintenance of gamma band activity in these cells.