1Fundamentals

Microscopic Anatomy of the Nervous system . . . 1

Elements of Neurophysiology . . . 4

Elements of Neurogenetics . . . 5

Microscopic Anatomy of the Nervous System

Neurons are the structural and functional building blocks of the nervous system. This type of cell is specialized for the reception, integration, and transmission of electrical impulses.

Neurons. The cell body (soma) of the neuron 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 cell body. They provide the cell with a much larger surface area than the cell body alone, thereby increasing the area available for intercellular contact and for the deployment of cell

membrane receptors. Different types of neurons have different characteristic morphological types of dendrites; those of the cerebellar Purkinje cells, for example, resemble a deer’s antlers (Fig. 1.2). The axon is a single cell process, usually longer than a dendrite, which emerges from the cell body at the axon hillock. It conducts efferent impulses away from the cell body to another neuron or an effector organ.

Generally speaking, every neuron has a soma, an axon, and one or more dendrites. The structure and configuration of the nerve cell processes (especially the dendrites) vary depending on the function of the neuron. Thus, neurons can be classified into a number of morphological subtypes (Fig. 1.3).

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Fundamentals

Fig. 1.1 Fine structure of a neuron

(after Wilkinson, J.L.: Neuroanatomy for Medical Students, 2nd edn, Butterworth−Heinemann, Oxford 1992).

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		Dendrites
	Mitochondrion	Nuclear membrane
	Rough endoplasmic	Smooth endoplasmic
		reticulum
	reticulum
		Nucleolus
		Nuclear pore
		Sex
		chromosome
	Free ribosomes	Golgi apparatus

Axonal membrane

Neurotubules and neurofilaments

Node of Ranvier

Myelin sheath

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2 1 Fundamentals

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

Neuroglia. The neurons constitute the important functional part of the nervous system; they are surrounded by supportive cells, which are collectively called neuroglia. Neuroglial cells of one particular type, the astrocytes, have a starlike morphology. They make contact with nonsynaptic sites on the neuronal surface and possess perivascular foot processes that contact 85 % of the capillaries of the nervous system. Astrocytes ensure

an adequate supply of nutrients to the neurons and are an important component of the blood−brain barrier. Other types of supportive cell in the central nervous system include the oligodendrocytes, microglia, and ependymal cells, and the cells of the choroid plexus.

Myelin sheaths. Axons less than 1 μm in diameter are usually unmyelinated, while thicker axons are sheathed in myelin. The myelin sheath is generated by the “sinking” of an axon into an oligodendrocyte (or, in the peripheral nervous system, a Schwann cell), forming a mesaxon, which consists of a double sheet of cell membrane. The mesaxon wraps around the axon multiple times (Fig. 1.4c). Individual segments of myelin, which can be up to 1 mm long, are separated by the intervening nodes of Ranvier, which play an important role in the transmission of nerve impulses along the axon (p. 4). The “naked” axonal segments at the nodes of Ranvier, are 1−4 μm wide and are only partly covered by processes of the neighboring Schwann cells. They are thus separated from the surrounding endoneural interstitium only by the neuronal cell membrane (neurilemma or axolemma). The nodal axolemma mainly contains voltage-dependent sodium channels, while the internodal segments mainly contain potassium channels.

Synapse. The sites at which neurons transmit impulses to each other are called synapses. Each synapse is composed of a bulblike expansion of 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. 1.5). Myelinated axons lose their myelin sheath just proximal to the axon terminal. A single neuron can receive synaptic input from one or many axons; the impulses it receives can be either exci-

Axon

Soma

Soma

Dendrites

Axon hillock

Fig. 1.3 Three types of neurons.

The arrows indicate the usual direction of impulse conduction (after Wilkinson, J.L.: Neuroanatomy for Medical Students, 2nd ed, Butterworth− Heinemann, Oxford 1992).

Axon

Dendrite

unipolar

bipolar

multipolar

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Microscopic Anatomy of the Nervous System

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Fundamentals

Fig. 1.4 Peripheral nerve (schematic drawings). a Low magnification reveals the plexuslike structure of the nerve fascicles. b The nerve fascicles (1) are surrounded by a common epineurium (2) composed mainly of fat and connective tissue. Blood vessels (vasa nervorum) lie between the fascicles (3 = arteries, 4 = veins). The fascicles are subdivided by septa derived from the perineurium (5). The endoneurium (6) contains myelinated fibers (7) and capillaries (8). c Electron microscopy reveals the flat perineural cells (9), which are tightly connected to one another by zonulae occludentes (10 =

tight junctions) and desmosomes (11). The perineural cell cytoplasm contains many pinocytotic vesicles (12). Within the endoneurium, one can discern myelinated (13) and unmyelinated axons (14), Schwann cells (15), a fibrocyte (16), and a capillary (17 = endothelial cell). The endoneural interstitium contains numerous collagen fibrils (18). The perineural, endothelial, and Schwann cells are surrounded by a basal membrane (19). A mesaxon (20) is formed by the sinking of an axon into a Schwann cell.

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4 1 Fundamentals

Axonal membrane

Neurotubules

Synaptic vesicles

Mitochondrion

Presynaptic

membrane

Synaptic

cleft

Postsynaptic

membrane

tatory or inhibitory. An axon can form a synapse onto a cell body, a dendrite, or another axon. Ongoing processes of structural and functional change at the synaptic contacts between nerve cells provide the nervous system with functional adaptability (“plasticity”) even after the individual 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, p. 263) or glandular cells (p. 280).

Fig. 1.5 Fine structure of a synapse (diagram after Wilkinson, J.L.:

Neuroanatomy for Medical Students, 2nd edn, Butterworth−Heinemann, Oxford 1992).

Elements of Neurophysiology

The resting membrane potential of a neuron or muscle cell 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 and chemical impulse transmission at the synapses are the specific mechanisms used by the nervous system for information transfer.

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., on the postsynaptic membrane) open only when a specific ligand binds to them, e. g., the neurotransmitter molecule that conveys neural impulses from cell to cell. These channels are called ligand-de- pendent ion channels. Voltage-dependent ion channels, on the other hand, are found mainly on the axonal membrane. They open and close depending on the transmembrane electrical potential.

Resting potential. A difference of electrical potential arises across the neuronal membrane because of the unequal concentrations of ions in the intracellular and extracellular spaces (ICS, ECS) combined with the varying electrical conductivity of the membrane to different types of ion. The resting potential is mainly determined by the ratio of intracellular and extracellular potassium concentration, because, 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. The inner surface of the membrane thereby loses positive charges and becomes negatively charged. As negative charge builds up on the inner surface of the membrane, a differ-

ence of electrical potential is generated, which opposes further outward flow of potassium ions; negative charge continues to build up until the potential difference exactly cancels out the force arising from the difference in potassium ion concentration. The net effect is that there is no further net transfer of potassium ions across the membrane in either direction and a stable, resting membrane potential is generated, with a value ranging from − 60 to − 90 mV.

Action potential. The sodium ion concentration is roughly 20 times higher in the ECS than in the ICS. Therefore, neurotransmitter-induced opening of ligandsensitive 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 positive value ranging from + 20 to + 50 mV. After a brief delay, the potassium channels of the cell membrane become more permeable than at rest, so that a net outflow of potassium ions results. This compensates for the preceding sodium influx and causes repolarization of the membrane to its resting potential. An active sodium pump also participates in this process. Until repolarization is complete, the membrane is temporarily unable to conduct any further impulses; the initial absolute refractory period is followed by a relative refractory period.

Impulse conduction. The axon potential begins at the axon hillock and is then conducted forward along the axonal membrane by the successive opening of voltagedependent sodium channels. This wave of excitation (local depolarization) travels down the axon at a speed that depends on the thickness of the axon and the thickness of its myelin sheath. The nodes of Ranvier play an especially important role in this process: the isolating myelin sheaths lower the capacitance of the axonal

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