Chapter Two - Role of Electrical Activity of Neurons for Neuroprotection

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Abstract

Neurons of the central nervous system (CNS) of adult mammals can be damaged in a variety of ways. Most neurons rapidly die after injury. Even if the injured CNS neurons do not die in a short time, the neurons eventually die because they are not able to regenerate their axons to reconnect with their normal targets. In addition, neurons are normally not replaced. Therefore, much work has been directed toward understanding of the molecular regulation of the CNS degeneration following injury, and different experimental strategies are being used to try to protect the damaged neurons. Following axonal lesion, the neurons not only need to survive but also to reconnect to be functionally relevant, and efforts are directed toward not only survival but also axonal regeneration and proper rewiring of injured neurons. Recent experimental data suggest that electrical activity, endogenous or exogenous, can enhance neuronal survival and regeneration in vitro and in vivo. This chapter reviews the evidence that have been obtained on the role of neuronal electrical activity on neuroprotection. We will develop perspectives toward neuroprotection and regeneration of adult lesioned CNS neurons based on electrical activity-dependent cell survival that may be applicable to various diseases of the CNS.

Introduction

Electrical activity plays an important role in promoting survival of injured neurons in the nervous systems. Evidence from many studies of different parts of the nervous systems in vivo and in vitro support the idea that a loss of electrical activity leads to neuronal death, and exogenous electrical activity can enhance neuronal survival (Corredor and Goldberg, 2009, Goldberg, 2012, Goldberg and Barres, 2000, Linden, 1994, Mennerick and Zorumski, 2000). Much research has focused on the neurotrophic effects that promote axonal regeneration, that is, neurite outgrowth, in different neurons of the peripheral nervous system (PNS) and central nervous system (CNS) during normal development and after injury.

Significant progress has been made in understanding the mechanism underlying the neuroprotective effects of electrical activity on various types of neurons in vitro and in vivo. There have also been significant advances in the past decade in the development of neuroprostheses that can help restore sensory function and communication that should aid humans with damage to the visual system. This new branch of experimental neuroscience, called brain–machine interface (BMI), offers the possibility of helping people with severe sensory and motor disabilities to interact better with the world and thus improve their quality of life.

Much attention has been focused on the relationship between the electrical activity of neurons and neuroprotection. I will review recent studies concerning the role of electrical activity of neurons on neuroprotection, discuss the possible mechanisms for the neuroprotection, and introduce the results of electrical stimulation treatments.

Section snippets

Importance of Neuronal Activity During Normal Development

It is well accepted that programmed cell death (PCD) occurs during normal development of the vertebrate nervous system. During the embryonic development of the vertebrate nervous system, approximately one-half of all neurons that are produced die by PCD. This appears to be a strategy of the CNS to adapt neuronal populations to their innervation target size and specificity. This naturally occurring neuronal death has been documented for many areas of both the central and PNSs of various species (

CNS Neurons Lose Neuronal Activity After Injury

After injury or in eyes with neurodegenerative diseases of the mammalian CNS, the CNS neurons cannot regenerate their axons to their targets and die relatively quickly. They are not replaced from a pool of progenitor or stem cells. In the visual system, for example, RGC axons injured in the optic nerve (ON) fail to regenerate back to the brain and often die after injury (Goldberg & Barres, 2000). The RGCs lose their trophic responsiveness after axotomy in vivo (Shen, Wiemelt, McMorris, &

Survival-Promoting Effects of Electrical Activity on Neurons In Vitro

In in vitro studies of the neuroprotective effects of neuronal activity, the neurons were activated by depolarizing the neurons by high extracellular potassium (K+). In addition, drugs such as forskolin were applied to elevate the cAMP levels, or electrical stimulation was used to activate the neurons.

Survival-Promoting Effects of Electrical Activity on Neurons In Vivo

In in vivo studies of the neuroprotective effects of neuronal activity, different methods have been used to increase the electrical activity of neurons, for example, direct electrical stimulation of the nervous system, or normal physiological stimulation such as exercise and light exposure, that stimulate the entire nervous system.

Mechanism of Neuroprotective Effects of Electrical Activity on CNS

Many studies have been performed to try to determine the mechanism for activity-dependent neuronal survival. The brain consists of neurons and glial cells that influence each other and collaborate to keep the brain functional and to perform a wide range of complex tasks. I will review the mechanisms of neuroprotection of neuronal activity on the entire CNS.

Conclusions: Significance of Activity-Dependent Survival

A vast amount of data has been collected on the neuronal activity-dependent neuroprotection (Fig. 2.1). Much progress has been achieved in understanding the mechanisms on how electrical activity enhances neuroprotection. Neuronal activity exerts neuroprotective effect directly on the neurons or through neural networks by inducing endogenous neuroprotective agents or transferring these agents to each other. Neuronal activity also acts on glial cells to induce the production or release of

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