C.B., an emergency room nurse, was well until, at 23 years of age, she noticed blurred vision in her left eye. Twenty-four hours later, her vision had dimmed, and a day later, she was totally blind in her left eye. A neurologist found a normal neu rologic examination. A magnetic resonance scan demon strated severa l a reas of demyeli nation in the su bcortical white matter of both cerebral hemispheres. Despite the per sistence of these a bnorma lities, C.B. recovered ful l vision in 4 weeks.
A yea r later, C.B. had weakness in her legs, associated with tingling in her right foot. Her physician told her that she probably had multiple sclerosis. She recovered 3 weeks later with only mild residual weakness.
After a symptom-free interval for 2 years, C.B. noticed the onset of double vision and a tremor that was worse when she attem pted to perform vol u nta ry actions ("intention tremor"). On examination, the neurologist found signs sug gesting demyelination in the brain stem and cerebellum. Again, the patient recovered with only mild resid ua.
C.B.'s history is typica l for patients with the relapsing remitting form of multiple sclerosis. This disorder, which oc curs in young adults {20-SO years old), is due to inflamma tory destruction of mye l i n sheaths with i n the CNS. Th is demyelination occurs in wel l-defined lesions (plaques) that a re disseminated i n space and i n time (hence, the term "multiple sclerosis"). Remyelination, withi n the core of the demyelination plaques, occurs sl uggishly if at a l l.
The relapsing-remitting course exemplified by C.B. pres ents an i nteresti ng exa mple of functional recovery in a neurologic disorder. How does recovery occur? Recent stud ies have demonstrated molecular plasticity of the demyeli nated axon membrane, which develops increased numbers of Na+ channels in regions that were formerly covered by the myelin sheath. This permits impulses to propagate in a contin uous, slow manner (similar to nonmyelinated axons) along demyelinated regions of some axons. The slowly con ducted impu lses ca rry enough information to support clin ical recovery of some functions, such as vision, even though the axons remain demyelinated.
does not involve neurotransmitters. Synaptic delay is shorter at electrical synapses than at chemical synapses. Whereas electrical synapses occur commonly in t he CNS of inframammalian species, they occur only rarely in the mammalian CNS.
The second broad class of synapse, which accounts for the overwhelming majority of synapses in the mammalian brain and spinal cord, is the chemical synapse. At a chem ical synapse a distinct cleft (about 30 nm wide) represents an extension of the extracellular space, separating the pre and postsynaptic membranes. The pre- and postsynaptic
FIGURE 3-9 Atrophy (loss of m uscle mass) i n the hands of a patient with hereditary sensorimotor neuropathy. Peripheral neuropathies affect the longest nerve fibers first, and the f eet and hands thus are affected i n early stages of the disease. (Courtesy of Dr. Catherina Faber.)
components at chemical synapses communicate via diffu sion of neurotransmitter molecules; some common trans mitters that consist of relatively small molecules are listed with their main areas of concentration in the nervous system in Table 3-5. As a result of depolarization of the presynaptic ending by action potentials, neurotransmitter molecules are released from the presynaptic ending, diffuse across the synaptic cleft, and bind to postsynaptic recep tors. These receptors are associated with and trigger the opening of (or, in some cases, closing of) ligand-gated ion channels. The opening (or closing) of these channels pro duces postsynaptic potentials. These depolarizations and hyperpolarizations are integrated by the neuron and deter-
TABLE 3-2 Nerve Fiber Types in Mammalian Nerve.
Fiber
mine whether it will fire or not (see Excitatory and In hibitory Synaptic Actions section).
Neurotransmitter in presynaptic terminals is contained in membrane-bound presynaptic vesicles. Release of neuro transmitter occurs when the presynaptic vesicles fuse with the presynaptic membrane, permitting release of their con tents by exocytosis. Vesicular transmitter release is triggered by an influx of Ca2+ into the presynaptic terminal, an event mediated by the activation of presynaptic Ca 2+ channels by the invading action potential. As a result of t his activity-in duced increase in Ca2+ in the presynaptic terminal, there is phosphorylation of proteins called synapsins, which appear to cross-link vesicles to the cytoskeleton, thereby preventing
Conduction Diameter Velocity Spike Duration (ms) Absolute Refractory Period (ms)
Fiber Type Function (mm)
Proprioception; somatic motor 1 2-20
Touch, pressure 5-1 2
Motor to muscle spindles 3-6
Pain, temperatu re, touch 2-5
Preganglionic autonomic <3
C dorsal root Pain, reflex responses 0.4-1 .2 sympathetic Postganglionic sympathetics 0.3-1 .3
Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 22nd ed. McGraw·Hi/1, 2005.
(m/s) 70-1 20 30-70 1 5-30 1 2-30 3-1 5 0.5-2 0.7-2.3 0.4-0.5 1 .2 2 2 0.4-1 1 .2 2 2
26 SECTION I Basic Principles
TABLE 3-3 Numeric Classification Sometimes Used
for Sensory Neurons. Number I a b Ill IV Origin
Muscle spindle, annulospiral ending Golgi tendon organ
Muscle spindle, flower-spray ending; touch, pressure Pain and temperature receptors; some touch receptors
Pain and other receptors
Fiber Type
A cr A cr
A J3
A 'O
Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 22nd ed. McGraw-Hiil, 2005.
their movement. This action permits fusion of vesicles with the presynaptic membrane, resulting in a rapid release of neurotransmitter. The release process and diffusion across the synaptic cleft account for the synaptic delay of 0.5 to 1 .0 ms at chemical synapses. This sequence is shown in diagram matic form at the neuromuscular junction, a prototypic synapse, in Figure 3-10.
SYNAPTIC TRANSMISSION
Directly Linked (Fast)
Transmitter molecules carry information from the presynap tic neuron to the postsynaptic neuron by binding at the post synaptic membrane with either of two types of postsynaptic receptor. The first type is found exclusively in the nervous sys tem and is directly linked to an ion channel (a ligand-gated ion channel). By binding to the postsynaptic receptor, the transmitter molecule acts directly on the postsynaptic ion channel. Moreover, the transmitter molecule is rapidly
TABLE 3-4
Chemical
Electrical (rare in mammals)
Modes of Synaptic Transmission.
Directly coupled (fast)