Fundamentals

1.1 Microscopic Anatomy of the Nervous System

Introduction

Neurologic diseases can only be understood on the basis of the anatomy and physiology of the nervous system. Genetic abnormalities underlie many of them. Modern methods such as electron microscopy, electrophysiologic testing, and biochemical and molecular-biological analysis have yielded new insights into neural structure and function that are playing an increasingly important role in the classification and diagnosis of nervous diseases, as well as in their treatment.

It follows that a basic knowledge of neuroanatomy (both gross and microscopic), neurophysiology, and neurogenetics is indispensable for contemporary medical practice. In this chapter, we briefly recapitulate the essential facts in these three areas.

For the student, the important questions are:

What are the microscopic building blocks of which the nervous system is composed?
What are the fundamental processes in neurophysiology?
What role do genetic factors play in the pathogenesis of disease?

The last question is becoming ever more important. Many neurologic diseases are hereditary, that is, partly or entirely due to genetic abnormalities; they will come to the reader’s attention again and again in the pages of this book. At present, in the era of molecular biology, the genetic defects underlying many of them have already been identified (with still more to come). For these diseases, diagnosis by deoxyribonucleic acid (DNA) testing is now possible even before the patient develops any overt symptoms. Such testing should be done only after the patient has been thoroughly informed of the potential consequences.

1.1 Microscopic Anatomy of the Nervous System

Key Point

Neurons are the structural and functional building blocks of the nervous system. They are specialized for the reception, integration, and transmission of electric impulses.

1.1.1 Neurons

The neuronal cell body (soma) is enclosed by the cell membrane and contains the cell nucleus, mitochondria, endoplasmic reticulum, neurotubules, and neurofilaments ( ▶ Fig. 1.1). Dendrites are short, more or less extensively branched cellular processes that conduct afferent impulses toward the soma. They provide the cell with a much larger surface area than the soma alone, thereby increasing the area available for intercellular contact and for the deployment of cell membrane receptors. Each type of neuron has its own characteristic dendritic structure: the dendritic tree of a cerebellar Purkinje cell, for example, resembles a deer’s antlers ( ▶ Fig. 1.2). The axon is a single, elongated cell process that emerges from the soma at the axon hillock. It conducts efferent impulses away from the soma to another neuron or to an effector organ.

Fig. 1.1 Fine structure of a neuron. (Adapted from Schuenke et al. Thieme Atlas of Anatomy. Head and Neuroanatomy. New York, NY: Thieme Medical Publishers; 2011. Illustration by Markus Voll.)

Fig. 1.2 Cerebellar Purkinje cell (microphotograph). Note the numerous synapses on the dendrites. (Image provided courtesy of Dr. Marco Vecellio, Histological Institute of the University of Fribourg, Switzerland.)

In general, every neuron has a soma, an axon, and one or more dendrites. The structure and configuration of the neuronal processes (especially the dendrites) vary depending on the function of the neuron. Thus, neurons can be classified into several morphologic subtypes ( ▶ Fig. 1.3).

Fig. 1.3 Three types of neurons. (Adapted from Schuenke et al. Thieme Atlas of Anatomy. Head and Neuroanatomy. New York, NY: Thieme Medical Publishers; 2011. Illustration by Markus Voll.)

1.1.2 Neuroglia

The neurons are traditionally thought to constitute the important functional part of the nervous system; they are surrounded by supportive cells, which are collectively called neuroglia. Astrocytes are neuroglial cells with a starlike structure. They make contact with nonsynaptic sites on the neuronal surface and also have perivascular foot processes that make contact with 85% of the capillaries of the nervous system. The astrocytes supply nutrients to the neurons and are an important constituent of the blood–brain barrier. Other types of supportive cell in the central nervous system are the oligodendrocytes, microglia, ependymal cells, and choroid plexus cells.

1.1.3 Myelin Sheaths

Axons less than 1 µm in diameter are usually unmyelinated; thicker ones are sheathed in myelin. The myelin sheath is generated when an axon “sinks” into an oligodendrocyte, giving rise to a mesaxon, that is, a double sheet of oligodendrocyte membrane. (In the peripheral nervous system, Schwann cells play the role of oligodendrocytes.) The mesaxon wraps around the axon multiple times to create the myelin sheath, a thick coat of electrically insulating material. Individual myelin segments (up to 1 mm long) are separated by segments of “naked” axon called nodes of Ranvier, which play an important role in impulse propagation (see section ▶ 1.1.4). The nodes are 1 to 4µm wide and are only partly covered by processes of the neighboring Schwann cells. They are thus separated from the endoneural interstitium by little more than the neuronal cell membrane (called the neurilemma or axolemma). The nodal axolemma mainly contains voltage-dependent sodium channels; the axonal segments between the nodes mainly contain potassium channels.

1.1.4 Synapses

The sites at which neurons transmit impulses to each other are called synapses. The structures making up a synapse include: a bulblike expansion at the end of an axon, called an axon terminal (or bouton); the synaptic cleft; and the postsynaptic membrane of the receiving neuron or effector organ ( ▶ Fig. 1.4). Myelinated axons lose their myelin sheath just proximal to the axon terminal. A single neuron can receive synaptic input from one or more axons, and the impulses it receives can be either excitatory or inhibitory. An axon can form a synapse onto a cell body, a dendrite, or another axon. Ongoing structural and functional changes at the synapses give the nervous system functional adaptability (“plasticity”) even after the organism has reached maturity. Neural impulses are transmitted across synapses by chemical substances called neurotransmitters: some of the more important ones in the central nervous system are dopamine, serotonin, acetylcholine, and γ-aminobutyric acid (GABA). Specialized synapses connect the axons of the peripheral nervous system to effector organs such as muscle cells (motor end plates, see section ▶ 15.1.3) or secretory cells in glands.

Fig. 1.4 Fine structure of a synapse. The two most common types of synapse are shown: 1 a spiny synapse and 2 a parallel contact or bouton en passage. (Reproduced from Schuenke et al. Thieme Atlas of Anatomy. Head and Neuroanatomy. New York, NY: Thieme Medical Publishers; 2011. Illustration by Markus Voll.)

1.2 Elements of Neurophysiology

Key Point

The resting membrane potential of a neuron or myocyte can undergo a rapid, transient change, called an action potential, in response to an incoming stimulus or impulse. The action potential is generated by transient changes of ion permeability across the cell membrane. Action potentials along neuronal processes and chemical impulse transmission between neurons at synapses are the mechanisms used by the nervous system for information transfer.

1.2.1 Ion Channels

Neurons are enclosed by a double-layered cell membrane with an inner phospholipid layer and an outer glycoprotein layer. Specialized protein molecules within the cell membrane form channels that are selectively permeable to sodium, potassium, or chloride ions. Some ion channels (e.g., in synapses) open only when a specific ligand binds to them, for example, a neurotransmitter molecule. These channels are called ligand-dependent ion channels. Voltage-dependent ion channels, on the other hand, are found mainly on axons. They open and close depending on the transmembrane electric potential.

1.2.2 Resting Potential

An electric potential difference arises across the neuronal membrane because of the unequal concentrations of ions in the intracellular and extracellular spaces (ICS, ECS), combined with the varying electric conductivity of the membrane to different types of ion. This resting potential is mainly determined by the ratio of intra- to extracellular potassium concentration. Its origin can be explained as follows. At rest, the membrane is highly permeable to potassium ions and relatively impermeable to sodium ions. The potassium concentration in the ICS is roughly 35 times higher than in the ECS. Thus, potassium ions tend to diffuse out of the cell. A buildup of negative charge on the inner surface of the membrane results; this, in turn, generates a difference of electric potential across the membrane that opposes further potassium ion outflow. An equilibrium is reached at which the potential difference exactly cancels out the force arising from the difference in potassium ion concentration. As there is no further net transfer of potassium ions across the membrane, the resting membrane potential remains stable, with a value ranging from –60 to –90 mV.

1.2.3 Action Potential

Because the sodium ion concentration is roughly 20 times higher in the ECS than in the ICS, the neurotransmitter-induced opening of ligand-sensitive postsynaptic sodium channels is followed by a rapid influx of sodium ions into the cell. The inner surface of the cell membrane becomes positively charged, and an action potential is generated whose amplitude and time course are independent of the nature and intensity of the depolarizing impulse (this is the all-or-nothing law of cellular excitation). The transmembrane potential difference reaches a peak ranging from +20 to +50 mV. Then, after a brief delay, the cell membrane becomes more permeable to potassium, and a net outflow of potassium ions results. This compensates for the preceding sodium influx and causes membrane repolarization. An active sodium pump also participates in this process. Until repolarization is complete, the membrane cannot conduct any further impulses; there is an initial absolute refractory period, followed by a relative refractory period.

1.2.4 Impulse Conduction

The axon potential begins at the axon hillock and is conducted along the axonal membrane by the successive opening of voltage-dependent sodium channels. This wave of excitation (local depolarization) travels down the axon at a speed depending on the thickness of the axon and the thickness of its myelin sheath. The nodes of Ranvier play a major role in this process: the myelin sheaths lower the capacitance of the axonal membrane and raise its electric resistance. The action potentials are therefore initiated only at the nodes of Ranvier, “jumping over” the internodal segments (so-called saltatory conduction). This mechanism enables myelinated nerve fibers to conduct action potentials much more rapidly than unmyelinated fibers. The normal motor and sensory conduction velocity of peripheral nerves is 50 to 60 m/s.