Intracellular transport

Turnover of membranous and skeletal materials takes place in all cells. In neurons, fresh components are continuously synthesized in the soma and moved into the axon and dendrites by a process of anterograde transport. At the same time, worn-out materials are returned to the soma by retrograde transport for degradation in lysosomes (see also target recognition, later).

Anterograde transport is of two kinds: rapid and slow. Included in rapid transport (at a speed of 300–400 mm/day) are free elements such as synaptic vesicles, transmitter substances (or their precursor molecules), and mitochondria. Also included are lipid and protein molecules (including receptor proteins) for insertion into the plasma membrane. Included in slow transport (at 5–10 mm/day) are the skeletal elements, and soluble proteins including some of those involved in transmitter release at nerve endings. Microtubules seem to be largely constructed within the axon. They are exported from the soma in preassembled short sheaves that propel one another along the initial segment of the axon; further progress is mainly by a process of elongation (up to 1 mm apiece) performed by the addition of tubulin polymers at their distal ends, with some disassembly at their proximal ends. The bulk movement of neurofilaments slows down to almost zero distally; there, the filaments are refreshed by the insertion of filament polymers moving from the soma by slow transport.

Retrograde transport of worn-out mitochondria, SER, and plasma membrane (including receptors therein) is fairly rapid (150–200 mm/day). In addition to its function in waste disposal, retrograde transport is involved in target cell recognition. At synaptic contacts, axons constantly ‘nibble’ the plasma membrane of target neurons by means of endocytotic uptake of protein-containing signaling endosomes. These proteins are known as neurotrophins (‘neuron foods’). They are brought to the soma and incorporated into Golgi complexes there. In addition, uptake of target cell ‘marker’ molecules is important for cell recognition during development. It may also be necessary for viability later on, because adult neurons shrink and may even die if their axons are severed proximal to their first branches.

The longest-known neurotrophin is nerve growth factor, on which the developing peripheral sensory and autonomic systems are especially dependent. Adult brain neurons synthesize brain-derived neurotrophic factor (BDNF) in the soma and send it to their nerve endings by anterograde transport. Animal studies have shown that BDNF maintains the general health of neurons in terms of metabolic activity, impulse propagation, and synaptic transmission.

Transport mechanisms

Microtubules are the supporting structures for neuronal transport. Microtubule-binding proteins, in the form of ATPases, propel organelles and molecules along the outer surface of the microtubules. Distinct ATPases are used for anterograde and retrograde work. Retrograde transport of signaling endosomes is performed by the dynein ATPase. Failure of dynein performance has been linked to motor neuron disease, described in Chapter 16.

Neurofilaments do not seem to be involved in the transport mechanism. They are rather evenly spaced, having side arms that keep them apart and provide skeletal stability by attachment to proteins beneath the axolemmal membrane. Neurofilament numbers are in direct proportion to axonal diameter, and the filaments may in truth determine axonal diameter.

Some points of clinical relevance are highlighted in Clinical Panel 6.1.

Receptor activation

Transmitter molecules cross the synaptic cleft and activate receptor proteins that straddle the postsynaptic membrane (Figure 6.8). The activated receptors initiate ionic events that either depolarize the postsynaptic membrane (excitatory postsynaptic effect) or hyperpolarize it (inhibitory postsynaptic effect). The voltage change passes over the soma in a decremental wave called electrotonus, and alters the resting potential of the first part or initial segment of the axon. (See Ch. 7 for details of the ionic events.) If excitatory postsynaptic potentials are dominant, the initial segment will be depolarized to threshold and generate action potentials.

Figure 6.8 Dynamic events at two types of nerve terminal. (A) Small molecule transmitter, exemplified by a glutamatergic nerve ending. (1) Carrier vesicles containing synaptic vesicle membrane proteins are rapidly transported along microtubules and stored in the plasma membrane of the terminal bouton. At the same time, enzymes and glutamate molecules are conveyed by slow transport. (2) Vesicle membrane proteins are retrieved from the plasma membrane and form synaptic vesicles. (3) Glutamate is taken into the vesicles, where it is stored and concentrated. (4) Loaded vesicles approach the presynaptic membrane. (5) Following depolarization, the ‘docked’ vesicles undergo exocytosis. (6) Released transmitter diffuses across the synaptic cleft and activates specific receptors in the postsynaptic membrane. (7) Vesicular membranes are retrieved by means of endocytosis. (8) Some glutamate is actively transported back into the bouton for recycling. (B) Neuropeptide cotransmission. The example here is peptide substance P cotransmission with glutamate, a combination found at the central end of unipolar neurons serving pain sensation. (1) The vesicles and peptide precursors (propeptides) are synthesized in Golgi complexes in the perikaryon and taken to the terminal bouton by rapid transport. (2) As they enter the bouton, peptide formation is being completed, whereupon the vesicle approaches the plasma membrane. (3) Following membrane depolarization, the vesicular contents are sent into the intercellular space by means of exocytosis. (4) Glutamate is simultaneously released into the synaptic cleft.

In the CNS, the commonest excitatory transmitter is glutamate; the commonest inhibitory one is gamma-aminobutyric acid (GABA). In the peripheral nervous system, the transmitter for motor neurons supplying striated muscle is acetylcholine; the main transmitter for sensory neurons is glutamate.

The sequence of events involved in glutamatergic synaptic transmission is shown in Figure 6.8A. In the case of peptide cotransmission with glutamate, release of (one or more) peptides is non-synaptic, as shown in Figure 6.8B.

Many sensory neurons liberate one or more peptides in addition to glutamate; the peptides may be liberated from any part of the neuron, but their usual role is to modulate (raise or lower) the effectiveness of the transmitter.

A further kind of transmission is known as volume transmission. This kind is typical of monoamine (biogenic amine) neurons, which fall into two categories. One category synthesizes a catecholamine, namely norepinephrine (noradrenaline) or dopamine, both synthesized from the amino acid tyrosine. The other synthesizes serotonin, derived from tryptophan. As illustrated in Figure 6.9, for dopamine, the transmitter is liberated from varicosities (where they are also synthesized) as well as from synaptic contacts. The transmitter enters the extracellular fluid of the CNS and activates specific receptors up to 100 μm away before being degraded. The monoamine neurons have enormous territorial distribution, and deviation from normal function is implicated in a variety of ailments including Parkinson disease, schizophrenia, and major depression.

Figure 6.9 Volume transmission in the brain. The axons of a glutamatergic neuron (1) and of a dopaminergic neuron (2) are making conventional synaptic contacts on the spine of a spiny stellate cell (3) in the striatum. Dopamine (DA) is also escaping from a varicosity and diffusing through the extracellular space (ECS) to activate dopamine receptors on the dendritic shaft and on the wall of a capillary pericyte (see Ch. 5).

Nitric oxide (a gaseous molecule) within glutamatergic neurons is also associated with volume transmission. Excess nitric oxide liberation is cytotoxic, notably in areas rendered avascular by cerebral arterial thrombosis. Glutamate itself is also potentially cytotoxic.

In the context of volume transmission, the conventional kind is called ‘wiring’ to indicate its relatively fixed nature.

Lock and key analogy for drug therapy

The receptor may be likened to a lock, the transmitter being the key that operates it. The transmitter output of certain neurons may falter as a consequence of age or disease, and a duplicate key can often be provided in the form of a drug that mimics the action of the transmitter. Such a drug is called an agonist. On the other hand, excessive production of a transmitter may be countered by a receptor blocker – the equivalent of a dummy key that will occupy the lock without activating it.

Inhibition versus disinhibition

Spontaneously active neurons are often held in check by inhibitory neurons (usually GABAergic), as shown in Figure 6.10A. The inhibitory neurons may be silenced by others of the same kind, leading to disinhibition of the target cell (Figure 6.10B). Disinhibition is a major feature of neuronal activity in the basal ganglia (Ch. 33).

Figure 6.10 Disinhibition. (A) Excitatory neuron 1 is activating inhibitory neuron 2 with consequent silencing of neuron 3 by neuron 2. (B) Interpolation of a second inhibitory neuron (2b) has the opposite effect on neuron 3, because 2b is silenced. Neuron 3 (spontaneously active unless inhibited) is released.

Less common chemical synapses

Two varieties of axoaxonic synapses are recognized. In both cases, the boutons belong to inhibitory neurons. One variety occurs on the initial segment of the axon, where it exercises a powerful veto on impulse generation (Figure 6.11). In the second kind, the boutons are applied to excitatory boutons of other neurons, and they inhibit transmitter release. The effect is called presynaptic inhibition, any conventional contact being postsynaptic in this context (Figure 6.12).

Figure 6.11 Axoaxonic synapses in the cerebral cortex. Arrows indicate direction of impulse conduction.

Figure 6.12 (1) Presynaptic and (2) postsynaptic inhibition of a spinal neuron projecting to the brain. Arrows indicate directions of impulse conduction (relay cell may be silenced by inhibitory cell activity).

Dendrodendritic (D-D) synapses occur between dendritic spines of contiguous spiny neurons, and alter the electrotonus of the target neuron rather than generating nerve impulses. In one-way D-D synapses, one of the two spines contains synaptic vesicles. In reciprocal synapses, both do. Excitatory D-D synapses are shown in Figure 6.13. Inhibitory D-D synapses are numerous in relay nuclei of the thalamus (Ch. 25).

Figure 6.13 Dendrodendritic excitation. The dendrites belong to three separate neurons. On the right is a reciprocal synapse. Arrows indicate direction of electrotonic waves.

Somatodendritic and somatosomatic synapses have also been identified, but they are scarce.

Myelination

Myelination commences during the middle period of gestation, and continues well into the second decade. A single oligodendrocyte lays myelin on upward of three dozen axons by means of a spiraling process whereby the inner and outer faces of the plasma membrane form the alternating major and minor dense lines seen in transverse sections of the myelin sheath (Figure 6.15). Some cytoplasm remains in paranodal pockets at the ends of each myelin segment. In the intervals between the glial wrappings, the axon is relatively exposed, at nodes.

Figure 6.15 Myelination in the central nervous system. Arrows indicate movement of the growing edge of the cytoplasmic flange of oligodendrocytes.

Myelination greatly increases the speed of impulse conduction, because the depolarization process jumps from node to node (see Ch. 9). During myelination, K⁺ ion channels are deleted from the underlying axolemma. For this reason, demyelinating diseases such as multiple sclerosis (Clinical Panel 6.3) are accompanied by progressive failure of impulse conduction.

Figure CP 6.3.1 An MRI scan of a 28-year-old man with multifocal demyelination secondary to multiple sclerosis. Axial T₂-weighted image showing multiple lesions of high signal intensity in the white matter. On the left side of the brain, at least five of these plaques are periventricular.

(Kindly provided by Dr. Joe Walsh, Department of Radiology, University College Hospital, Galway, Ireland.)

Unmyelinated axons abound in the gray matter. They are fine (0.2 μm or less in diameter) and not individually ensheathed.