The Neuron

Generalities.

    The neuron is the basic unit of the nervous system. This is the cell type that transmits information, using electrical impulses, between the brain and our body. In addition to neuron, our brain contains two more cell types, astrocytes and microglia, respectively performing housekeeping and immune functions. All neurons do not look alike; some are short, being only 1 mm long, and others can reach up to one meter. Most of them conduct electricity in only one direction, but some can send messages to several other neurons at once. The figure below shows some types of neuron that could be found in our brain.

Examples of different types of neurons.

    The figure on the left shows a typical neuron and describes its main components. The soma, the cell structure containing the nucleus, is where the molecules/proteins are produced. This is also where the neurotransmitters are synthesized, and then transported to the nerve terminals where they will be released to transmit their information.

    Then. on one end of the neuron, we have the dendrites that receive chemical from other neurons, afferent neurons. On the other end, there are hundreds of endings participating to the release of neurotransmitters which will then excite or inhibit the next cell. It is the sum of these electric currents, positive and negative, transmitted to the dendrites of a neuron, that determines whether an action potential (a positive electrical signal) will be initiated at the hillock.

    Thereafter, the action potential will travel along the axon, acting as a long electrical wire, to the nerve endings. Most axons are surrounded by a discontinuous layer of myelin (Schwann cells wrapped around the axon). This myelin serves as the wire insulation and helps to accelerate the electrical conduction. When the action potential reaches the endings, it triggers the release of neurotransmitters that propagate the message to the next neurons.

The resting potential.

     Like almost all cells in our body, the neuron has an electrical potential in relation to the extracellular environment. That is, positive and negative ions are not distributed equally on each side of the cytoplasmic (cellular) membrane. That difference of charges between the intra- and the extracellular milieu, at rest, determines the resting potential. Note that, although this section particularly concerns neurons, other cell types can be electrically active, such as the myocytes (muscle cells).

     The cell membrane is made up of two layers of lipid (fat) which does not really allow hydrophilic substances (water-soluble substances) to pass through, and is electrically neutral and insulating. Within this membrane, however, there are proteins that can act as pores (channels), that open and close to let certain negatively or positively charged ions pass through. And, there are other proteins that transport or pump these ions from one side of the membrane to the other side. More specifically, and probably the most important one, there is a pump that expels three sodium (3Na+) and brings back in two potassium (2K+) ions in exchange. And, it is the unequal distribution of these ions and the permeability of the membrane for these ions that causes the cell, even at rest, to be electrically polarized; that is there is a difference in electrical potential between the intra- and extracellular milieu. And, given that the neuron membrane is not very permeable to Na+, the membrane remains polarized. This potential, at rest when the cell is inactive, is called the resting potential.

     In the beside table, you will find a typical representation of the distribution, at rest, of the main ions on both sides of the membrane of a neuron. The electric potential generated for each ion is given by the Nernst equation which reads:

     In the Nernst equation above, E is the electrical potential, in volts, for the ion 'X', R is the gas constant (8.314 J * mol^-1 * K^-1), T is the temperature in °K (37°C = 310.15° K), z is the valence of ion 'X', F is Faraday's constant (96,485.34 C * mol^-1), [X]_o is the extracellular concentration of ion 'X', and [X]_i is the intracellular concentration of the ion 'X'.

The action potential.

     The action potential (nerve impulse) is the electrical current that travels along the neuron's axon to transmit a signal to another one or more neurons, or to any other excitable cells such as muscle cells. Changes in membrane potentials first occur locally and at low intensities. But, when the depolarization of the neuron is sufficient, when at the trigger zone it reaches a certain threshold, the neuron produces a strong electrical potential which is the action potential.

     At rest, the membrane popential (difference of electrical charges intracellularely compared to the extracellular milieu) is said to be polarized at approximately -70 to -90mV. When the membrane potential becomes less negative or even positive, the neuron is said to depolarize. But when the membrane potential becomes more negative, the neuron is said to undergo hyperpolarization.

     It is usually at the level of the dendrites of the neuron that, under the stimulating or inhibitory action of neurotransmitters or other stimuli, that short-term modifications occur which locally modify the membrane potential. The more intense the stimulus, the greater the depolarization, or hyperpolarization, will be. It is important, here, to note that the lipid (fatty) nature of the membrane opposes the propagation of electric current so that a weak electric current will only travel a very short distance (1-2mm) along of the membrane before completely fading; a more intense current will travel a greater distance (4-5mm at most). This is the principle of membrane resistance and capacitance.

    As mentioned, for the neuron to trigger an action potential, sufficient stimulation (exceeding a certain threshold) must reach a region of the neuron called the trigger zone. This region is usually located at the beginning of the axon. Therefore, larger the depolarization occuring at the proximal level of the dendrites (near the cell body, or near the trigger zone), the more likely this depolarization will be able to generate an action potential that will then travel along the axon.

     When depolarization, at the trigger zone, reaches a certain threshold, this causes a series of reactions which leads to the generation of the action potential. Sodium (Na+) channels, which are dependent on the membrane potential, will open up when local membrane potential reaches certain threshold voltage (dotted line in the figure on the left). Their opening will result in a massive entry of sodium (sodium current; yellow line in the figure) into the cell, and these positive ions will further depolarize the interior of the cell to a voltage of approximately +30mV compared to the extracellular milieu. The sodium channels open for only a millisecond or so, and then they close immediately. When the membrane potential shifts positively, this now causes the potassium (K+) channels to open up and the potassium, present in high concentration in the cell, will flow out of the cell (potassium current; green line in the figure), and this will repolarize the cell. Often, following the action potential, there is a slight phase of hyperpolarization making the neuron a little more negative, hence a little more difficult to depolarize and reach the threshold voltage again. So immediately after an action potential, a second action potential is more difficult to generate. This is called the refractory period when the neuron cannot be or is more difficult to reactivate. Finally, during the resting phase, between two action potentials, thousands of sodium-potassium pumps (Na+/K+ ATPase) expel the sodium that had entered and reintroduce the potassium that had exited, this in order to restore the ionic concentrations that was present at rest.

Propagation of nerve impulses.

     To transmit information, the propagation of the action potential takes place all along the axon toward the terminals where the electrical signal will be converted into a chemical signal. When the axon does not have myelin sheaths, propagation occurs all along the axon and relatively slowly. But when the axon is myelinated, the propagation is called saltatory; the action potentials 'jump' from one node of Ranvier to the other, allowing for much better conduction velocity.

     When the sum of the electric currents reaches a threshold voltage at the trigger zone, the generated action potential will diffuse towards a neighboring membrane region so that this neighboring region will in turn depolarize it to also reach the threshold voltage, and generate a new action potential. Thus, the nerve impulse will move away from its point of origin and will travel along the axon towards the nerve endings.

     If the intensity of the stimulus is important and if it lasts long enough, it is the number of action potentials, hence the frequency of impulses, that will be more important. Note that the amplitude of these depolarizations will not change because the sodium channels close and the potassium channels open when the action potential voltage of approximately +25 mV - +30 mV is reached. This is what makes the amplitude of action potentials a 'all or nothing' phenomenon, meaning either an action potential will not be generated or if generated, it will a defined maximum voltage. Also, while the voltage-gated sodium channels are open and until they are fully reactivable, a second action potential cannot be induced; this is the absolute refractory period. But, as soon as the membrane is repolarized, it is possible to initiate a new action potential.

     Following the absolute refractory period follows a relative refractory period. During this period, it is possible to induce a second action potential, but only if the amplitude of the stimulus is sufficient to counteract the late hyperpolarization and bring the membrane potential above the excitation threshold.

     With a strong enough stimulus, the membrane potential is maintained above the threshold and the frequency of the nerve impulse will increase accordingly. By using variation in impulses frequency, neurons can translate different stimulus intensities.

      The wave of depolarization, which propagates continuously (from one area of the axonal membrane to the neighbor area), only occurs in unmyelinated axons, or in myocytes (muscle cells). This is the slowest form of current propagation. In fact, the speed of propagation depends on two factors: the diameter of the axon and the presence of myelin (Schwann cell) around the axon. The larger the diameter of the axon, the faster the conduction. It's a bit like an electric wire; a large diameter offers less resistance, because there is more surface area for ionic exchanges.

     The speed of propagation is the fastest in myelinated axons. The myelin acts as an insulator around the axon and prevents the leakage of ionic charges. In those myelinated axons, it is only between the Schwann cells (the cells wrapping the axon, the myelin) that ionic exchanges can occur. We call these spaces between two Schwann cells, the nodes of Ranvier. It is in these spaces that we find the greatest concentrations of voltage-sensitive sodium channels. This causes the nerve impulse to jump from node of Ranvier to another node (jumps of approximately 1mm distance) and propagate very quickly, up to 130 m/s. This is called the saltatory current.

Saltatory conduction of nerve impulses.

     Depending on their axon diameter, their degree of myelination and their speed of propagation of the nerve impulses, the neurons are classified into three main categories. The Type A fibers are the largest and are well myelinated, they propagate nerve impulses at highest speeds of 15 to 130 m/s. These are mainly the sensory and motor fibers innerving the skin, the skeletal muscles and the joints. The Type B fibers are of intermediate diameter and are lightly myelinated; they propagate nerve impulses at speeds of 3 to 15 m/s. These are mainly the fibers of the autonomic nervous system which innervate the viscera and other sensory fibers. The Type C fibers are small in diameter and have no myelin; they propagate nerve impulses at speeds of 1 m/s at most. They are mainly the fibers which carry nociceptive (pain) information.

     Finally, other factors, such as the cold or the lack of oxygen (due to hypoxia or reduced blood flow), can also influence the speed of propagation of the action potential, they slow it down.

The synapse.

     The synapse is the junction between two neurons. The synapse includes both the receiving and emitting components of a neuron: the emitting end of a neuron (the presynaptic nerve ending), and the receiving end of the next neuron (the dendrites). At the presynaptic nerve ending, the signal is transmitted, often by a chemical signal (neurotransmitter). On the postsynaptic cell (often the dendrites of a neuron, or the neuromuscular junction of a myocyte) there are receptors which receive the chemical information. Beside chemical synapses, which are the most common, there are another type of synapses which electrically transmits its signal. The later are commonly found between the cardiomyocytes and are called gap junctions.

     Electrical synapses are relatively few in number. These are regions where the membranes of two neurons (or other electrically active cells like cardiomyocytes for example) are in very close contact; there is only 3.5 nm of space between the two membranes. These regions are called gap junctions. These regions are made up of multiple channels where ions can circulate freely and transmit nerve impulses very quickly to the next cell. These synapses are particularly useful to allow synchronization of electrical activity between several neurons, or other networks of electrically active cells like for the cardiomyocytes. In the figure on the left, we can see a photograph of these channels taken by electron microscopy (A), and a representation of one such junction (B).

     Chemical synapses, on the other end, are the most common synapses. We often say they are the classical synapses by opposition to the gap junction. It is through these chemical synapses that nerve impulses normally pass from one neuron to another, or from one neuron to its target cell (like for a myocyte). There are two components to a synapse: the nerve ending of the presynaptic neuron (the neuron where the information comes from), and the receptor region of the postsynaptic neuron (the neuron that receives the information). The space (30 to 50 nm) between the nerve ending and the receptor region is called the synaptic cleft.

     When the nerve impulse from the presynaptic neuron arrives at the terminal, it induces the opening of voltage-gated calcium channels and the entry of calcium (Ca++) which in turn causes the release of a neurotransmitters (chemical transmission). The neurotransmitter is contained in vesicles which fuse with the presynaptic membrane and release their content, by exocytosis, into the synaptic cleft. Then, the neurotransmitter diffuses into this cleft and eventually bind to specific receptors located on the membrane of the postsynaptic neuron. This interaction causes the opening of local ion channels, inducing an electrical current that may, if of sufficient intensity, will propagate through the postsynaptic neuron. The postsynaptic receptors, receiving the neurotransmitters, are of two types, they can be ionotropic or metabotropic. If they are ionotropic, the receptors are themselves ion channels and the action of the neurotransmitter is directly activating/opening these ion channels. If they are metabotropic, the receptors act indirectly (via a second messenger) to nearby ion channels.

     By comparing the electrical synapses (gap junctions) and the chemical synapses, we can immediately note two important differences. First, for the chemical synapse, the transmission of nerve impulses can only occur in one direction; from the terminal of the presynaptic neuron to the receiving area of the postsynaptic neuron, while the current can be bidirectional in the gap junction. Also, for the chemical synapse, there is a certain delay (0.3 to 0.5 ms) in the transmission of the impulse, because there are many steps to go through, including the diffusion of neurotransmitters through the synaptic cleft.

     Also, depending on the nature of the neurotransmitter, the nature of the receptors on which it acts, and their coupling to specific ion channels, the current generated could be excitatory (Excitatory PostSynaptic Potential, EPSP) or inhibitory (Inhibitory PostSynaptic Potential, IPSP). It should also be noted that the potential generated will not be of the all-or-nothing type which depends on channels that are voltage-dependent, but it will rather be a gradual change in electrical potential. This postsynaptic current will depend mainly on the quantity of neurotransmitter in the synaptic cleft, and this quantity of neurotransmitter will in turn depend on the frequency of action potentials arriving at the presynaptic terminal.

     In order to stop the postsynaptic excitation (or inhibition) process, the neurotransmitter must be removed from the synaptic cleft or inactivated. There are two mechanisms involved in the termination of this chemical signal. The neurotransmitter can be recaptured by the presynaptic terminal and recycled into new vesicles of the presynaptic terminal, or it can be neutralized by specific enzymes (e.g. acetylcholinesterase will break down the acetylcholine in the neuromuscular junction).

     Finally, on the postsynaptic neuron, there is not only one presynaptic neuron that can innervate it. There are in fact thousands of endings coming probably from several different neurons which will each exert their influence on the response of the postsynaptic neuron. Some of these inputs would be excitatory while others could be inhibitory. It is the sum of all these excitatory and inhibitory currents which will determine, if it reach threshold current at the trigger zone, whether the postsynaptic neuron will eventually generate an action potential toward the next neuron of a pathway.

The neurotransmitters.

     The neurotransmitters are those molecules in the nerve endings of a presynaptic neuron which, under the influence of the nerve impulse, will be released into the synaptic cleft and influence the electrical activity of a postsynaptic neuron. There are several types of neurotransmitters, and there are also other molecules that can, not necessarily trigger action potential in the postsynaptic neuron, but influence its the electrical activity or their excitability. The latter are generally called neuromodulators (can also include certain hormones). Here, I am only providing a summary table of the main neurotransmitters and some neuromodulators. Note the following abbreviations: CNS = Central Nervous System; PNS = Preripheral Nervous System; ANS = Autonomic Nervous System.

List of the main neurotransmitters and neuromodulators (only a short summary).

Neurotransmitters	Receptors	Functionnal classes	Site of secretion	Notes
Acetylcholine (Ach)	Nicotinic receptors - skeletal muscles, ganglions et CNS	Excitatory - direct action	CNS - cortex, brain, hippocampus and brainstem PNS - all skeletal muscles - some other terminals ANS - preganglionic fibers - postganglionic parasympathetic fibers	- inactivated by the acetylcholinesterase - Botox inhibits its release - atropine blocks its binding to muscarinic receptors - curare blocks its binding to nicotinic receptors - nicotine on the nicotinic receptors promotes the release of dopamine, and hence addiction
	Muscarinics - viscera and CNS	Excitatory or inhibitory - depending on the receptor types - indirect action via second messengers
Biogenic amines
Norepinephrine (NE) or Noradrenaline (NA)	Adrenergic - α1, α2 - β1, β2, β3	could be excitatory or inhibitory depending on the receptor they act indirect action via second messagers (G protein-coupled receptors)	CNS - locus ceruleus, limbic system, certain regions of the cortex PNS - postganglionic fibers of the sympathetic system	- well-being sensation - antidepressants, amphetamines, cocaine and Ritalin, increase its activity - reserpine reduces its concentration in the brain and causes depression
Dopamine (DA)	Dopaminergic - D1, D5 - D2, D3, D4	Excitatory or inhibitory depending on the type of receptor Indirect action (via second messengers)	CNS - substantia nigra of the midbrain, hypothalamus, secondary motor pathways PNS - certain sympathetic ganglia	- feeling of well-being - L-dopa, amphetamines, nicotine, cannabis, cocaine and Ritalin increase its activity - insufficient production in Parkinson's disease - increased release in schizophrenics
Serotonin (5-HT)	Serotoninergic - 5-HT3 - 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, 5-HT7	Generally inhibitory Direct action for 5-HT3 Indirect action for others (via second messengers)	CNS - brainstem: midbrain, hypothalamus, limbic system, cerebellum, pineal gland (epiphysis), spinal cord	- different roles in sleep, appetite, nausea, migraine and mood - prolonging its action (using Prozac, Paxil or others inhibitors of the serotonin reuptake) relieves anxiety and depression - LSD blocks its activity and ecstasy stimulates it
Histamine	Histaminergic - H1, H2, H3, H4	Excitatory or inhibitory depending on the type of receptor Indirect action for others (via second messengers)	CNS - hypothalamus	- different roles in wakefulness, appetite, learning, memory - roles in inflammation, vasodilation and acid secretions of the stomach
Amino acids
Gamma-aminobutyric acid (GABA)	GABAergic - GABAa	Inhibitory - direct action	CNS - widespread in cortex, hypothalamus, cerebellum, spinal cord, olfactory bulb and retina	- main inhibitory neurotransmitter - antiepileptics, alcohol, Valium and certain sleeping pills potentiate its effect - reducing its action can cause convulsions
	GABAergic - GABAb	Inhibitory - indirect action (via second messengers)
Glutamate (Glu)	Ionotropic receptors - NMDA (NR1, NR2, NR3) - AMPA (GluR1 to GluR4) - KAR (GluR5 to GluR7, KA-1, KA-2)	generally excitatory - direct action	CNS - main excitatory neurotransmitter in the brain and spinal cord	- important role in learning and memory - excitotoxic during stroke - can promote tumor growth - involved in drug addiction
	Metabotropic receptors - mglu1 to mglu8	Excitatory and inhibitory - indirect action (via second messengers)
Glycine (Gly)	Ionotropic receptors - GlyR	Generally inhibitory - direct action	CNS - spinal cord, brainstem and retina	- main inhibitory neurotransmitter in the spinal cord - inhibiting its activity with strychnine can cause seizures and respiratory arrest
Peptides
Endorphins Dynorphins Enkephalins	Opiate receptors	Inhibitory in general - indirect action (via second messengers)	CNS - brain, hypothalamus, limbic system, pituitary gland, spinal cord	- reduce pain by inhibiting substance P - morphine, heroin and methadone exert similar effects
Tachykinins Substance P Neurokinin A (NKA)	Tachykinin receptors - TACR1 Neurokinin receptors - NK1, NK2, NK3	Excitatory - indirect action (via second messengers)	CNS - basal ganglia, midbrain, hypothalamus, cortex PNS - pain fibers	- activities of the respiratory and cardiovascular systems - mood control - nociception
Somatostatin	Somatostatin receptors - SSTR1 - SSTR5	Inhibitory in general - indirect action (via second messengers)	CNS - hypothalamus, septum, basal ganglia, hippocampus, cortex Pancreas	- actions on the digestive system - inhibits the release of growth hormone
Cholecystokinins (CCK)		Excitatory in general - indirect action (via second messengers)	CNS - throughout the CNS - small intestine	- roles in anxiety, pain and memory - appetite suppressant
Adenosines
ATP	Purinergic receptors - P2X - P2Y	Excitatory and inhibitory - direct action (P2X) - indirect (P2Y) (via second messengers)	CNS - basal nuclei PNS - dorsal root ganglia of the spinal cord	- released by sensory neurons - also involved in pain sensations
Adenosine	Receptors - A1, A2a, A2b, A3	Inhibitory in general - indirect action (via second messengers)	- throughout the CNS	- coffee, tea and chocolate stimulate its release - role in the sleep-wake cycle - dilation of arterioles
Gases and lipids
Nitrogen monoxide (NO)		Excitatory - indirect action (via second messengers)	CNS - brain and spinal cord PNS - adrenal glands, penile nerves ANS - presynaptic and postsynaptic neurons of the sympathetic and parasympathetic systems	- potentiates the damage caused by stroke - certain erectile problems and pulmonary edema are treated by increasing the action of NO, like with Viagra and similar
Carbon monoxyde (CO)		Excitatory - indirect action (via second messengers)	- brain - certain neuromuscular and neuroglandular synapses
Endocannabinoids Anandamide		Inhibitory - indirect action (via second messengers)	- throughout the CNS	- role in memory - regulation of appetite, nausea and vomiting - neuronal development