How does neural cell work?
Human brain is a quite mysterious system. It is comprised of about 10 billions of neural cells or neurons.
Figure 1. Pyramidal Neurons in cat's sensorimotor cortex. N.S.Kositzyn[1]
At the beginning it was thought that neurons work as switches. They may be in two states: "on" or "off". If neuron is "on", it sends signals to the other neurons. When neuron is "off", it does not send signals. Later, it was discovered that neuron is a very sophisticated system.
Figure 2. A pyramidal neuron. N.S.Kositzyn[1]
Excitatory Tissue and Membrane Potential.
Any excitatory tissue cell has membrane potential; its cell membrane is negative inside and positive outside. This membrane potential is called Resting Potential. How is it maintained?
Cell membrane has sodium-potassium pump, which pumps K+ ions in the cell and Na+ ions out of cell. If the cell membrane were permeable to K+ and Na + ions, K+ ions would passively flow back outside and Na + ions would passively flow back inside to restore original equilibrium.
In fact, cell membrane is much less permeable to Na + ions than to K+ ions. Membrane has K channels and Na channels. These channels may be closed or open depending on membrane potential.
During Resting Potential, Na channels are closed and K channels are open. K+ ions flow passively outside and accumulate positive charge. Na + ions cannot flow inside or its flow is insignificant.
When positive K+ ions leave the cell, it becomes negative inside. Negative charge attracts positive K+ ions and some of them flow back inside. When charge force (inside direction) and force due to gradient concentration of K+ (outside direction) become equals, equilibrium develops. Some insignificant Na+ flow decreases membrane potential. That is how Resting Potential is maintained. Please see figure. 3
Figure 3. Membane potentials at rest and exitement
When negatively charge electrode applied to cell surface, resting potential starts decreasing. This condition is called depolarization. When depolarization reaches a threshold, Na + channels open in cell membrane. Since Na+ concentration is higher outside than inside the cell, force due to gradient concentration will make Na+ flow inside. Besides, negative charge inside the cell will attract positive Na+ ions. So, both forces make Na+ ions flow inside the cell and now Na+ flow is much greater than K+ flow outside. As a result, cell membrane becomes positive inside and negative outside. Action Potential is generated.
Please see figure 3. and 4. Membrane potential is measured by inserting inside the cell a tiny glass capillary filled with KCL solution. This capillary has a wire inside, which is connected to an amplifier and a display.
Figure 4. Action Potential
Resting potential is about 0. 90 volt. Action Potential is about 0.120 volt. It depends on type and size of a cell.
Hodgkin and Huxley [3,4,5,6,7] studied membrane potentials on the giant axon of a squid, which is one millimeter in diameter. They changed membrane potential and found that permeability of membrane depends on membrane potential. Depolarization causes opening Na+ channels. Action potential is generated, than Na+ channels are closing again. K+ ions flow outside becomes greater than Na+ ions flow inside and membrane potential restores back to Resting Potential.
Action potential in neuron or skeletal muscle cell lasts about one millisecond. In heart, smooth muscle cell membrane has Ca+ channels. Ca++ channels open after opening Na channels. Ca++ ions flow inside and cause muscle contraction. Ca++ channel blockers cause relaxation of vascular smooth muscles and lower blood pressure.
Neural cell and synapses
Neural cell or neuron has many dendrites, which look like trees and serve for input information. One long outgrowth - axon serves for output information. The body of neural cell and its dendrites are covered with thousand of synapses - contacts from the other neurons.
Figure 5. Dendrites covered by synapses. Synapse. N.S.Kositzyn[1]
Through this synapses dendrites receive messages from the other neurons. These messages can inhibit or increase neuron activity. In the last case, neuron may generate action potential, which spreads along the axon.
Axon terminal forms synapse, a structure comprised of axon terminal, presynaptic membrane, synaptic cleft and postsynaptic membrane. Please see figure 6.
Figure 6. Synaptic Transmission
Synapse contains vesicles with neurotransmitter. When action potential reaches axon terminal , its membrane becomes permeable to Ca++ ions. Ca++ ions flow inside the terminal and cause vesicles to move to presynapric membrane and release transmitter in synaptic cleft. Please see figure 6.
Transmitter molecules passively spread in synaptic cleft and reach postsynaptic membrane receptors. Transmitter binds to receptors and change potential of postsynaptic membrane. Message is transferred to the next neuron or muscle cell.
There are many different neurotransmitters or neuromediators: norepinephrine, dopamine, serotonin, acetylcholine, gamma-aminobutiric acid (GABA), glutamine, etc.
Some transmitters affect ion channels, some use a second messager (adenyl cyclase cAMP).
Some transmitters are inhibitory some are excitatory; some are either, depending on receptor type.
Inhibitory mediators increase K+ or Cl - flow, which increase membrane potential. Excitatory mediators increase Na+ flow and cause depolarization of the membrane, as a result, an action potential may be generated in the next neuron if the axon ends on a neuron or in muscle cell if the axon ends on a muscle cell.
Mediators' action is stopped when mediator molecule is modified by an enzyme, or due to reuptake of mediator by axon terminal.
In case when mediator is acetylcholine, it is deactivated by acetylcholine esterase. It breaks acetylcholine to choline and acetate. The axon terminal reuptakes choline from synaptic cleft by choline pump and acetylcholine is synthesized again from choline and acetylCoA.
Acetylcholine system is impaired in patients with Alzheimer disease.
There are two acetylcholine receptors: muscarinic and nicotinic. Muscarinic receptors bind muscarin and nicotinic receptors bind nicotine. For example, brain and heart cells have muscarinic receptors and skeletal muscle tissue has nicotinic receptors.
In case, when mediator is norepinephrine, axon terminal reuptakes it from synaptic cleft. Enzyme monoamineoxidase (MAO) oxidizes norepinephrine. MAO inhibitors are used as antidepressants because they increase concentration of brain norepinephrine , which is low in depressed patients. Neurons, which synapses produce norepinephrine are located in brain stem in an area, which is called a locus coeruleus - blue spot. it is known that rats with electrodes inserted in blue spot, or in fibers, which go out of blue spot, stimulate their own brain. It was proofed that this brain area belongs to the rewarding system.[2]
Also neurons, which are located in raphe nuclei of the brain stem, produce serotonin. It is known that raphe nuclei control sleep and low serotonin concentration in brain may cause anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) inhibit serotonin reuptake from synaptic cleft and increase serotonin extracellular concentration. SSRI are used as antidepressants in the treatment of depression and anxiety. Lexapro, Selexa and Zoloft are most known SSRI in the USA.
Norepinephrine receptors are divided on two types: alpha and beta. There are two types of alpha receptors excitatory alpha1, inhibitory alpha2 and three types of beta receptors: excitatory beta1, inhibitory beta2, beta3. Heart has beta1 receptors that is why beta blockers decrease heart rate and force.
Dopamine receptors are divided on two types: D1 and D2. Substantia Nigra in brain stem contains neurons, which axon terminals produce dopamine. Excess dopamine production is related to schizophrenia. Lack of dopamine is observed in Parkinsonism.
Understanding of mechanisms of synaptic transmission and metabolism of neuromediators will help us to develop new safe medications and to understand conditions underlying different psychotic or somatic diseases.
1.Professor Nicolay Kositzyn from Moscow institute of Highest Nervous Activity and Neurophysiology kindly gave me permission to use pictures from his monograph: Microstructure of dendrites and axodendritic relations in the cerebral nervous system. Moscow 1976
REFERENCES:
2. Catherine H Bielajew, Tamara Harris. Self-Stimulation: A Rewarding Decade
J. Psychiatr Neurosci, Vol.16, No 3, 1991
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1188317&blobtype=pdf
3. Huxley AL and Hodgkin AF. Measurement of Current-Voltage Relations in the Membrane of the Giant Axon of Loligo. Journal of Physiology 1: 424-448, 1952.
4. Huxley AL and Hodgkin AF. Currents Carried by Sodium and Potassium Ions Through the Membrane of the Giant Axon of Loligo. Journal of Physiology 1:449-472, 1952.
5. Huxley AL and Hodgkin AF. The Components of Membrane Conductance in the Giant Axon of Loligo. Journal of Physiology 1: 473-496, 1952 (c).
6. Huxley AL and Hodgkin AF. The Dual Effect of Membrane Potential on Sodium Conductance in the Giant Axon of Loligo. Journal of Physiology 1: 497-506,1952.
7. Huxley AF and Hodgkin AL. A Quantitative Description of Membrane Currentand Its Application to Conduction and Excitiation in Nerve. Journal of Physiology 1: 500-544, 1952.
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