7 DEVELOPMENT OF MYELINATION AND AXON ENSHEATHMENT

Neurons and Their Properties



11



Cell body of an oligodendrocyte (neurilemmal

cells play similar role in peripheral nervous system)



Cell membrane of

myelinated axon



Mitochondrion

in cytoplasm of

neuronal axon



Node of Ranvier



Minute masses of cytoplasm trapped

between fused layers of cell membrane

of oligodendrocyte



1.8  HIGH-MAGNIFICATION VIEW OF A CENTRAL

MYELIN SHEATH

Fused layers of oligodendroglial cell membrane wrap around

a segment of a central axon, preventing ionic flow across the

cell membrane for the entire myelinated segment. The node



Fused layers of cell membrane of oligodendrocyte wrapped

around axon of a myelinated neuron of central nervous

system (the lipid of lipoprotein constituting fused cell

membrane is myelin, which gives myelinated axon a white,

glistening appearance)



between two adjacent segments is bare axon membrane possessing Na+ channels. These nodes are sites where action potentials are reinitiated in the conduction of propagated action

potentials.



12



Overview of the Nervous System



Amino acid

synapse



Catecholamine

synapse

Glutamate



Presynaptic

receptor



Serotonin

synapse



Tyrosine

TH

L-Dopa

ALAAD



Tryptophan

TrH

5-OH-tryptophan



Presynaptic

receptor



Dopamine



ALAAD

5-OH-tryptamine

(serotonin)



DBH

Returned to

Krebs cycle



Norepinephrine

Metabolism



Metabolism



Metabolism

Diffusion



Uptake



Receptor



High-affinity

uptake carrier



High-affinity

uptake carrier



Metabolism

Diffusion



Receptor



Receptor



Returned to

Krebs cycle



Peptide

synapse



Peptide synthesized

in cell body



Acetylcholine

synapse



Acetyl CoA

from glucose

metabolism

Choline

ChAT

Acetylcholine



Peptidases



Receptor



Chemical neurotransmission



Acetylcholinesterase

rapidly hydrolyzes ACh

Receptor



Neurons and Their Properties



NEUROTRANSMISSION

1.9  CHEMICAL NEUROTRANSMISSION

AMINO ACID SYNAPSE



Amino acids used by a neuron as neurotransmitters are compartmentalized for release as neurotransmitters in synaptic

vesicles. The amino acid glutamate (depicted in this diagram)

is the most abundant excitatory neurotransmitter in the CNS.

Following release from synaptic vesicles, some glutamate binds

to postsynaptic receptors. Released glutamate is inactivated by

uptake into both pre- and postsynaptic neurons, where the

amino acid is incorporated into the Krebs cycle or reused for

a variety of functions.

CATECHOLAMINE SYNAPSE



Catecholamines are synthesized from the dietary amino acid

tyrosine, which is taken up competitively into the brain by a

carrier system. Tyrosine is synthesized into L-dopa by tyrosine

hydroxylase (TH), the rate-limiting synthetic enzyme. Additional conversion into dopamine takes place in the cytoplasm

via aromatic L-amino acid decarboxylase (ALAAD). Dopamine is taken up into synaptic vesicles and stored for subsequent release. In noradrenergic nerve terminals, dopamine

beta-hydroxylase (DBH) further hydroxylates dopamine into

norepinephrine in the synaptic vesicles. In adrenergic nerve

terminals, norepinephrine is methylated to epinephrine by

phenolethanolamine N-methyl transferase. Following release,

the catecholamine neurotransmitter binds to appropriate receptors (dopamine and alpha- and beta-�adrenergic receptors)

on the postsynaptic membrane, altering postsynaptic excitability, second-messenger activation, or both. Catecholamines

also can act on presynaptic receptors, modulating the excitability of the presynaptic terminal and influencing subsequent

neurotransmitter release. Catecholamines are inactivated by

presynaptic reuptake (high-affinity uptake carrier) and, to a

lesser extent, by metabolism (monoamine oxidase deamination and catechol-O-methyltransferase) and diffusion.

SEROTONIN SYNAPSE



Serotonin is synthesized from the dietary amino acid tryptophan, taken up competitively into the brain by a carrier

system. Tryptophan is synthesized to 5-hydroxytryptophan

(5-OH-tryptophan) by tryptophan hydroxylase (TrH), the

rate-�limiting synthetic enzyme. Conversion of 5-hydroxytryptophan to 5-hydroxytryptamine (5-HT, serotonin) takes

place in the cytoplasm by means of ALAAD. Serotonin is stored

in synaptic vesicles. Following release, serotonin can bind to

receptors on the postsynaptic membrane, altering postsynaptic excitability, second messenger activation, or both. Serotonin also can act on presynaptic receptors (5-HT receptors),

modulating the excitability of the � presynaptic � terminal and



13



influencing subsequent neurotransmitter � release. � Serotonin

is �inactivated by presynaptic reuptake (high-��affinity uptake

carrier) and to a lesser extent by metabolism and diffusion.

PEPTIDE SYNAPSES



Neuropeptides are synthesized from prohormones, large peptides synthesized in the cell body from mRNA. The larger

precursor peptide is cleaved posttranslationally to active neuropeptides, which are packaged in synaptic vesicles and transported anterogradely by the process of axoplasmic transport.

These vesicles are stored in the nerve terminals until released

by appropriate excitation-secretion coupling induced by an

action potential. The neuropeptide binds to receptors on the

postsynaptic membrane. In the CNS, there is often an anatomic mismatch between the localization of peptidergic nerve

terminals and the localization of cells possessing membrane

receptors responsive to that neuropeptide, suggesting that

the amount of release and the extent of diffusion may be important factors in neuropeptide neurotransmission. Released

neuropeptides are inactivated by peptidases.

ACETYLCHOLINE (CHOLINERGIC) SYNAPSE



Acetylcholine (ACh) is synthesized from dietary choline and

acetyl coenzyme A (CoA), derived from the metabolism of

glucose by the enzyme choline acetyltransferase (ChAT). ACh

is stored in synaptic vesicles; following release, it binds to cholinergic receptors (nicotinic or muscarinic) on the postsynaptic membrane, influencing the excitability of the postsynaptic

cell. Enzymatic hydrolysis (cleavage) by acetylcholine esterase

rapidly inactivates ACh.



CLINICAL POINT

Synthesis of catecholamines in the brain is rate limited by the availability of the precursor amino acid tyrosine; synthesis of serotonin, an

indoleamine, is rate limited by the availability of the precursor amino

acid tryptophan. Tyrosine and tryptophan compete with other amino

acids—phenylalanine, leucine, isoleucine, and valine—for uptake 

into the brain through a common carrier mechanism. When a good

protein source is available in the diet, tyrosine is present in abundance,

and robust catecholamine synthesis occurs; when a diet lacks sufficient protein, tryptophan is competitively abundant compared with

tyrosine, and serotonin synthesis is favored. This is one mechanism

by which the composition of the diet can influence the synthesis of

serotonin as opposed to catecholamine and influence mood and affective behavior. During critical periods of development, if low availability of tyrosine occurs because of protein malnourishment, central

noradrenergic axons cannot exert their trophic influence on cortical

neuronal development such as the visual cortex; stunted dendritic

development occurs, and the binocular responsiveness of key cortical neurons is prevented. Thus, nutritional content and balance are

important to both proper brain development and ongoing affective

behavior.



14



Overview of the Nervous System

A. Schematic of synaptic endings

Numerous boutons (synaptic knobs) of presynaptic neurons

terminating on a motor neuron and its dendrites

Dendrite

Neurofilaments

Axon hillock

Neurotubules

Initial segment

Axon

Node



B. Enlarged section of bouton



Axon (axoplasm)

Axolemma



Myelin sheath



Mitochondria

Dendrites

Glial process



Synaptic vesicles

Synaptic cleft

Presynaptic membrane (densely staining)

Postsynaptic membrane (densely staining)

Postsynaptic cell



1.10  SYNAPTIC MORPHOLOGY

Synapses are specialized sites where neurons communicate

with each other and with effector or target cells. A, A typical neuron that receives numerous synaptic contacts on its

cell body and associated dendrites. The contacts are derived

from both myelinated and unmyelinated axons. Incoming

myelinated axons lose their myelin sheaths, exhibit extensive

branching, and terminate as synaptic boutons (terminals) on

the � target (in this example, motor) neuron. B, An enlargement of an axosomatic terminal. Chemical neurotransmitters

are packaged in synaptic vesicles. When an action potential

invades the terminal region, depolarization triggers Ca2+ influx into the terminal, causing numerous synaptic vesicles to

fuse with the presynaptic membrane, releasing their packets of

neurotransmitter into the synaptic cleft. The neurotransmitter

can bind to receptors on the postsynaptic membrane, resulting

in graded excitatory or inhibitory postsynaptic potentials or in

neuromodulatory effects on intracellular signaling systems in

the target cell. There is sometimes a mismatch between the

site of release of a neurotransmitter and the location of target

neurons possessing receptors for the neurotransmitter (can be

immediately adjacent or at a distance). Many nerve terminals

can release multiple neurotransmitters; the process is regulated by gene activation and by the frequency and duration

of axonal activity. Some nerve terminals possess presynaptic



receptors for their released neurotransmitters. Activation of

these presynaptic receptors regulates neurotransmitter release. Some nerve terminals also possess high-affinity uptake

carriers for transport of the neurotransmitters (e.g. dopamine,

norepinephrine, serotonin) back into the nerve terminal for

repackaging and reuse.



CLINICAL POINT

Synaptic endings, particularly axodendritic and axosomatic endings,

terminate abundantly on some neuronal cell types such as LMNs. The

distribution of synapses, based on a hierarchy of descending pathways

and interneurons, orchestrates the excitability of the target neuron. If

one of the major sources of input is disrupted (such as the corticospinal tract in an internal capsule lesion, which may occur in an ischemic

stroke) or if damage has occurred to the collective descending UMN

pathways (as in a spinal cord injury), the remaining potential sources

of input can sprout and occupy regional sites left bare because of the

degeneration of the normal complement of synapses. As a result, primary sensory inputs from Ia afferents and other sensory influences,

via interneurons, can take on a predominant influence over the excitability of the target motor neurons, leading to a hyperexcitable state.

This may account in part for the hypertonic state and hyperreflexic

responses to stimulation of primary muscle spindle afferents (muscle

stretch reflex) and of flexor reflex afferents (nociceptive stimulation).

Recent studies indicate that synaptic growth, plasticity, and remodeling can continue into adulthood and even into old age.



Neurons and Their Properties



Extracellular fluid



+



Membrane



+



15



Axoplasm



–

–

–



Na�



–



+ Diffu



sio

n



+



–



+

ATP



anspo



ADP



rt



ti

A c ve

tr



+



Na�



Mitochondrion



ATPase



+

+

K�



D



n

sio

iffu



+



K�



–

–

–



+

Diffusion



Cl�



+



Cl�



–



+

+



–



+



gNa�1



_

Protein

(anions)



–



Resistance



gK�100



mV



EK

�90



mV



ECl

�70



gCl�50 to 150

+



ENa

�50



RMP

–70 mV



Equivalent circuit diagram;

g is ion conductance across

the membrane



mV



–



and Cl− of 145 and 105 mEq/L, Â� respectively, are high compared to the intracellular concentrations of 15 and 8 mEq/

1.11  NEURONAL RESTING POTENTIAL

L. The extracellular concentration of K+ of 3.5 mEq/L is low

Cations (+) and anions (−) are distributed unevenly across the compared to the intracellular concentration of 130 mEq/L.

neuronal cell membrane because the membrane is �differentially The resting potential of neurons is close to the equilibrium

permeable to these ions. The uneven distribution depends on potential for K+ (as if the membrane were permeable only to

the forces of charge separation and diffusion. The permeability K+). Na+ is actively pumped out of the cell in exchange for

of the membrane to ions changes with depolarization (toward inward pumping of K+ by the Na+-K+-ATPase membrane

0) or hyperpolarization (away from 0). The typical neuronal pump. Equivalent circuit diagrams for Na+, K+, and Cl−, calresting potential is approximately −90 mV with respect to the culated using the Nernst equation, are illustrated in the lower

extracellular fluid. The Â� extracellular Â� concentrations of Na+   diagram.



electrical properties



16



Overview of the Nervous System

Chemical Synaptic Transmission

Excitatory



A. Ion movements



Inhibitory

Synaptic vesicles

in synaptic bouton

Presynaptic membrane



+

–



+

–



Na+ +

–



K+



+

–



+

–



Transmitter substances



+

–



Synaptic cleft



Cl–



+

–



+

–



+

–



+

–



K+



Postsynaptic membrane

At inhibitory synapse, transmitter substance released

by an impulse increases permeability of postsynaptic

membrane to K+ and Cl– but not Na+. K+ moves out of

postsynaptic cell.



When impulse reaches excitatory synaptic bouton,

it causes release of a transmitter substance into

synaptic cleft. This increases permeability of

postsynaptic membrane to Na+ and K+. More Na+

moves into postsynaptic cell than K+ moves out,

due to greater electrochemical gradient.



Synaptic bouton



+

–



+

–



–

+



+

–



Resultant net ionic current flow is in a direction that

tends to depolarize postsynaptic cell. If depolarization

reaches firing threshold at the axon hillock, an impulse

is generated in postsynaptic cell.



+

–



+

–



+

–



+

–



Potential (mV)



Potential (mV)



–70



–70



0



8

12

16

msec

Current flow and potential change



+

–



Resultant ionic current flow is in a direction that tends

to hyperpolarize postsynaptic cell. This makes depolarization by excitatory synapses more difficult—more

depolarization is required to reach threshold.



B. EPSPs, IPSPs, and current flow



–65



+

–



0



4



msec

8



12



–75

Current flow

Potential change



4



1.12  GRADED POTENTIALS IN NEURONS

A, Ion movements. Excitatory and inhibitory neurotransmissions are processes by which released neurotransmitter, acting on postsynaptic membrane receptors, elicits a local or

Â�regional perturbation in the membrane potential: (1) toward 0 

(depolarization, excitatory postsynaptic potential; EPSP) via

an inward flow of Na+ caused by increased permeability of

the membrane to positively charged ions; or (2) away from 0 

(hyperpolarization, inhibitory postsynaptic potential; IPSP)

via an inward flow of Cl− and a compensatory outward flow

of K+ caused by increased membrane permeability to Cl−. Following the action of neurotransmitters on the postsynaptic



16



Current flow and potential change



membrane, the resultant EPSPs and IPSPs exert local influences that dissipate over time and distance but contribute to

the overall excitability and ion distribution in the neuron. It

is unusual for a single excitatory input to generate sufficient

EPSPs to bring about depolarization of the initial segment of

the axon above threshold so that an action potential is fired.

However, the influence of multiple EPSPs, integrated over

space and time, may sum to collectively reach threshold. IPSPs

reduce the ability of EPSPs to bring the postsynaptic membrane to threshold. B, EPSPs, IPSPs, and current flow. EPSPand IPSP-induced changes in postsynaptic current (red) and

potential (blue).



Neurons and Their Properties



17



Membrane potential (mV)



�20

Action potential



0



Na� conductance



K� conductance



�70

msec 0



0.5



Extracellular

fluid



Na�



K�



Cl�

�



�

�



Na�



�

�

�

�

�

�



K�



K�



Cl�

�40



Cl�



�

Stimulus

current



Stimulus current

produces depolarization

�



Stim.



Na�



1.0



Membrane



�

�



�

�



�

�



�

�



�

�



�

�



Axoplasm



Na�



Na�



K�



K�



Cl�

�

� �20

�

�

At firing level Na� conductance greatly increases,

giving rise to strong inward

Na� current, leads to

explosive positive feedback

with depolarization increasing

Na� conductance



�



�20



�

�



�

�



�

�



�

�



Cl�

� �75

�



Na�

�

K�

�

Cl�



Cl�

�

�



K�



�



�

Cl�

�



Na�



K� conductance increases,

causing repolarization; Na�

conductance returns to

normal



K�



K�



� �

�



�

�



Na�

�



�



�

�



�75



�

Na�

�



Cl�



�

�



�



�



�



�



Equivalent circuit diagrams



1.13  ACTION POTENTIALS

Action potentials (APs) are all-or-nothing, nondecremental,

electrical potentials that allow an electrical signal to travel for

very long distances (a meter or more) and trigger neurotransmitter release through electrochemical coupling (excitationsecretion coupling). APs are usually initiated at the initial

segment of axons when temporal and spatial summation of

EPSPs cause sufficient excitation (depolarization) to open

Na+ channels, allowing the membrane to reach threshold.

Threshold is the point at which Na+ influx through these Na+



channels cannot be countered by efflux of K+. When threshold is reached, an action potential is fired. As the axon rapidly

depolarizes during the rising phase of the AP, the membrane

increases its K+ conductance, which then allows influx of K+

to counter the rapid depolarization and bring the membrane

potential back toward its resting level. Once the action potential has been initiated, it rapidly propagates down the axon by

reinitiating itself at each node of Ranvier (myelinated axon) or

adjacent patch of membrane (unmyelinated axon) by locally

bringing that next zone of axon membrane to threshold.