Astrocyte-Dependent Slow Inward Currents (SICs) Participate in Neuromodulatory Mechanisms in the Pedunculopontine Nucleus (PPN)

Abstract

Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms.

Ketamine Within Clinically Effective Range Inhibits Glutamate Transmission From Astrocytes to Neurons and Disrupts Synchronization of Astrocytic SICs

“…The glutamate that spontaneously released from astrocytes produces slow inward currents (SICs) via the extrasynaptic, GluN2B-containing NMDA receptors on neighboring neurons (Shigetomi et al, 2008). When compared with the miniature excitatory postsynaptic currents (mEPSCs), SICs exhibit significantly slower rise and decay times (Kovacs and Pal, 2017). SICs persists when neuronal and synaptic activity is suppressed, and both pharmacological and mechanical stimulation of astrocytes can induce SICs in neighboring neurons (Angulo et al, 2004).…”

Autonomous Learning Paradigm for Spiking Neural Networks

“…Hence our SNN controller has one presynaptic neuron and two postsynaptic actuator neurons: the proposed autonomous learning algorithm will learn to respond with either a forward or left turn motion. A key signalling pathway is the slow inwards current (SIC) emitted by an excited astrocyte cell [10]. Because astrocyte interacts with many neurons we assume that the SIC continually stimulates both postsynaptic neurons, which propels the robot initially towards the obstacle.…”

And Then There Was Light: Perspectives of Optogenetics for Deep Brain Stimulation and Neuromodulation

“…The simplistic view of an imbalance between excitatory and inhibitory pathways must be complemented to take into account phenomena, such as retrograde activation, synchronicity in specific cells, interference with spontaneous (rhythmic) activity (Tass et al, 2012 ) and cell type activated (Witt et al, 2013 ). The role of astrocytes is well recognized but still difficult to integrate in our models (Kovacs and Pal, 2017 ). More and more, it is the limitations in physiological knowledge that impedes an optimal exploitation of techniques, such as optogenetics in the clinical world (Karas et al, 2013 ).…”