CoverModule 1.0. Homeostasis, Membranes, Electrophysiology and ANS1.1. Homeostasis1.1.1. Homeostasis Defined1.1.2. Homeostatic Control Systems1.1.3. Feedback Response Loop1.2. Cell Transport; Water & Solutes1.2.1. Fluid Compartments1.2.2. Osmosis1.2.3. Diffusion of Solutes1.2.4. Active Transport1.2.5. Bulk Transport1.3. Electrophysiology1.3.1. Ions and Cell Membranes1.3.2. Membrane Potentials1.3.3. Graded Potential1.3.4. Action Potentials1.3.5. Refractory Periods1.3.6. Propagation of an Action Potential1.4. The Synapse1.5. The Autonomic Nervous System1.5.1. Organization of the Nervous System1.5.2. Structural Organization of the ANS1.5.3. The SNS and the PNS1.5.4. The Enteric Nervous System1.5.5. Physiology of the ANS1.5.6. Neurotransmitters of the ANS1.5.7. Receptors of the ANS1.5.8. Actions of the Autonomic Nervous System1.5.9. Table of Actions for the SNS and PNS and Some Common DrugsModule 2.0. Skeletal Muscle and Special Senses2.1. Structural Organization of Skeletal Muscle2.2.1. Neuromuscular Junction, Excitation-Contraction Coupling2.2.2. Muscle Contractures and Cramps2.3. Whole Muscle Contraction, Fiber Type, Fatigue and Muscle Pharmacology2.3.1. Motor Units2.3.2. Factors that Influence the Force of Contraction2.3.2. Factors that Influence the Force of Muscle Contraction2.3.3. Energy Source for Muscle Contraction2.3.4. Skeletal Muscle Fiber Types2.3.5. Fatigue2.3.6. Muscle Pharmacology2.4. Smooth Muscle2.4.1. Smooth Muscle Contraction2.5. Control of Body Movement2.5.1. Voluntary Control of Muscle2.5.2. Reflexes2.6. Taste and Smell2.6.1. Taste2.6.2. The Sense of Smell2.7. Vision2.7.1. Structure of the Eye2.7.2. Focusing Light on the Retina2.7.3. Converting Light to Action Potentials2.7.4. The Retina2.7.5. Phototransduction2.7.6. Receptive Fields2.8. Hearing and Equilibrium2.8.1. The Nature of Sound2.8.2. The Hearing Apparatus2.8.3. Sound Vibrations to Action Potentials2.8.4. The Sense of Balance and EquilibriumModule 3.0. Cardiovascular System3.1. Structure of the Heart3.1.1. Chambers and Circulation3.2. Cardiac Cell Action Potentials3.2.1. Action Potentials in Cardiac Muscle Cells3.2.2. Action Potentials in Cardiac Autorhythmic cells3.2.3. Cellular Mechanisms of Inotropy and Chronotropy3.3. Electrophysiology of Heart Muscle3.3.1. Heart Conduction System3.3.2. Electrocardiogram (ECG)3.3.3. Abnormal ECG - Current of Injury3.4. The Cardiac Cycle3.4.1. Cardiac cycle3.4.2. Cardiac Measurements and Pressure Volume Loops3.5. Blood vessels and Blood Pressure3.5.1. Arteries and Veins3.5.2. Capillaries3.5.3. Blood Pressure Regulation and Shock3.5.4. Capillary Exchange3.5.5. Myogenic and Paracrine Regulation of Vasoconstriction and Vasodilation3.6. Blood3.6.1. Composition of Blood3.6.2. Hematopoeisis3.6.3. Breaking Down Red Blood Cells3.6.4. HemostasisModule 4.0. Urinary and Respiratory Systems4.1. Function and Structure of the Kidney4.1.1. Urinary System Function4.1.2. Functional Anatomy of the Urinary System4.1.3. The Nephron: Functional Unit of the Kidney4.1.4. The Renal Corpuscle: Bowman's Capsule4.2. Physiology of Urine Production4.2.1. Filtration4.2.2. Renal Clearance4.2.3. Tubular Reabsorption4.2.4. Urine Concentration and Dilution4.2.5. Hormonal Regulation of Urine Production4.3. Acid/Base Balance4.3.1. Buffers4.3.2. Acid/Base Disturbances4.4. The Respiratory System4.4.1. Respiratory System Structure and Function4.4.2. Respiratory Membrane4.4.3. Respiratory pressures and Inspriation/Expiration4.4.4. Alveoli and Surfactant4.4.5. Pneumothorax4.4.6. Pressure-Volume Loops and the Work of Breathing4.5. Gas Exchange and Transport4.5.1. Gas Laws4.5.2. Partial Pressure Gradients in the Lung4.5.3. Alveolar Gas Equation4.5.4. Oxygen and Carbon Dioxide Transport in the Blood4.5.5. Alveolar Ventilation4.5.6. Ventilation/Perfusion Ratio4.6. Chronic Bronchitis and Emphysema4.6.1. Respiratory Control by the Medulla Oblongata4.6.2. Chemicals that Regulate VentilationModule 5.0. Digestive, Endocrine and Reproductive Systems5.1. Functional Anatomy of the Digestive System5.1.1. Layers of the Digestive Tract5.1.2. Enteric Nervous System5.1.3. Organs of the Digestive System5.2. Digestion5.2.1. Carbohydrates5.2.2. Proteins5.2.3. Lipids5.2.4. Lipoproteins5.3. Regulation of Digestive Secretions5.4. Endocrine System5.4.1. Overview of the Endocrine System5.4.2. Hormone Receptors5.4.3. Hormones of the Body5.4.4. Other Hormones: Melatonin and Pheromones5.5. The Hypothalamus and Pituitary Gland5.5.1. Structure and Function of the Hypothalamus and Pituitary Gland5.5.2. The Posterior Pituitary5.5.3. The Anterior Pituitary5.5.4. Growth Hormone5.5.5. Prolactin5.5.6. Thyroid Hormones5.5.7. Adrenal Hormones5.6. Pancreas5.6.1. Insulin and Glucagon5.6.2. Diabetes Mellitus5.7. Reproductive System Anatomy5.7.1. Female Reproductive Anatomy5.7.2. Male Reproductive Anatomy5.7.3. Sexual Development at Puberty5.7.4. Male Reproductive Endocrine Axis5.7.5. Spermatogenesis5.7.6. Female Reproductive System: Oogenesis5.7.7. Ovulation and Fertilization5.7.8. The Ovarian Cycle5.7.9. The Uterine Cycle5.7.10. PregnancyAppendix A. GenderAppendix B. The Placebo EffectB.2.1. The Placebo EffectB.2.2. Examples of the Placebo EffectB.2.3. How do Placebos Work?B.2.4. Are Placebos Ethical?B.2.5. How do we validate actual effectiveness of placebosB.2.6. Tips for evaluating scientific evidenceB.2.7. What about Faith Healingstest chapter
1.4

The Synapse

Up to this point we have discussed how action potentials propagate down axons but not how they move between neurons. The transition from one neuron to another neuron will be the major topic of this section. This transition requires the introduction of three separate parts of the neuron, the dendrite, the soma and the axon terminal. Typically, voltage changes in neurons flow from dendrites, to the soma, and finally the axon. Dendrites are short, branched processes that extend from the cell body. Dendrites function to receive information and do so through numerous receptors located in their membranes that bind to chemicals called neurotransmitters. The cell body is the portion of the cell that surrounds the nucleus and plays a major role in synthesizing proteins. Once an axon reaches a target, it terminates into multiple endings, called axon terminals. The axon terminal is designed to convert the electrical signal into a chemical signal in a process called synaptic transmission. This transition occurs at a structure called the synapse.

Structurally, two types of synapses are found in neurons: chemical and electrical. Chemical synapses occur when neural membranes are very close together but remain distinct, leaving a space. Electrical synapses occur when membranes are linked together (gap junctions) via specialized proteins (connexins) that allow the flow of ions quickly from one cell to another. Electrical synapses are found in heart muscle. Because electrical synapses are rare in the nervous system, the remaining discussion will address the chemical synapse.

synapse.jpgPublic Domain by NIH https://commons.wikimedia.org/wiki/File:Generic_Neurotransmitter_System.jpg

As stated chemical synapses use chemicals called neurotransmitters to communicate the messages between cells. The part of the synapse that releases the neurotransmitter into the synapse is called the presynaptic terminal, and the part of the synapse that receives the neurotransmitter is called the postsynaptic terminal. The narrow space between the two regions is called the synaptic cleft. Both the presynaptic and postsynaptic terminals contain the molecular machinery needed to carry out the signaling process.

The presynaptic terminal contains large numbers of vesicles that are packed with neurotransmitter molecules. When an action potential arrives at the presynaptic terminal, due to the actions of voltage-gated Na+ channels, voltage-gated Ca2+  channels open, which allow for the influx of Ca2+  which then activates an array of molecules in the neuronal membrane and the vesicular membranes called SNARE proteins. These newly activated protein molecules then induce exocytosis of the vesicles, which results in the release of the neurotransmitter from the cell and into the synaptic cleft. There are a variety of different chemicals that have been shown or hypothesized to serve as neurotransmitters (ie., gases, purines, lipids, amino acids), specific examples include: norepinephrine, acetylcholine, serotonin, glutamate, gamma-aminobutyric acid (GABA), glycine and numerous small peptides, even ATP.

The neurotransmitter then binds to receptors located in the postsynaptic membrane and induces a conformational change. Depending on the receptor, the conformation change will induce a G-protein coupling cascade (metabotropic) or open an ion channel (ionotropic). The type of channel will ultimately determine the type of response that the cell experiences in response to the neurotransmitter. For ionotropic receptors, the conformation change will cause the receptor to act as a pore in the membrane for ions to move through. Metabotropic receptor activation will result in a G-protein cascade that activates or inhibits other intracellular proteins. Depending on the type of ion, the effect on the postsynaptic cell may be depolarizing (excitatory) or hyperpolarizing (inhibitory). Depolarizing signals are called excitatory postsynaptic potentials (EPSP) while inhibitory signals are called inhibitory postsynaptic potentials (IPSP).

To turn off the signal there are enzymes that reside in the synaptic cleft that breakdown and inactivate the neurotransmitters. The components of the neurotransmitter are then taken back up by the presynaptic terminal to be recycled to make more of the neurotransmitter.  An example of one of the enzymes is acetylcholinesterase that breaks down the neurotransmitter acetylcholine.

EPSP.png
An IPSP drives the membrane potential to a more negative value and an EPSP drives the membrane potential to a more positive value possibly hitting threshold to initiate an action potential.
Image by BYU-I student  2017
IPSP.png
IPSPs and EPSPs working at a cell soma
Image by BYU-I Becky T 2018

The net effect of all the EPSPs and IPSPs is experienced at a specialized structure called axon hillock. If threshold is reached at the axon hillock, then an action potential will continue down the axon. The ultimate goal of an EPSP is to cause enough change in the membrane to initiate an action potential. The goal of the IPSP is to cause a change in the membrane to prevent an action potential. Each EPSP or IPSP lasts a few milliseconds, and then, the membrane returns to the original resting membrane potential. Since the dendrite is non-myelinated, is very small in diameter, and has few if any voltage-gated Na+ channels, the Rm is low and the Ri is high, meaning that in many cases, a single EPSP is not sufficient to cause an action potential. Because of this, dendrites vary widely in length and diameter. In addition, dendrites can contain thousands of protrusions called dendritic spines. These spines serve to increase the number of possible contacts between neurons. In dendrites that are long and thin the sphere of influence from the Na+ ion experiences too much Ri to have a large effect. Therefore, many EPSPs from multiple synapses combine on a dendrite which results in a much larger voltage change that helps the sphere of influence reach the soma. This phenomenon is called spatial summation. EPSPs from the same synapse can also combine if they arrive in rapid succession; this phenomenon is called temporal summation. Requiring multiple EPSPs to fire an action potential is a way that neurons increase sensitivity and accuracy.

Although the soma is also unmyelinated and does not contain many voltage-gated Na+ channels, the large diameter of the soma makes Ri very small and the resultant length constant very large (equation 4). Thus, if a depolarizing stimulus arrives at the soma above threshold, it will continue through the soma without diminishing until it arrives at a special junction where the axon joins the soma called the axon hillock. The axon hillock has a large concentration of voltage-gated Na+ channels, the activation of which will start the action potential propagating down the axon. Some synapses are made directly on the soma itself, ensuring a suprathreshold depolarization when they are activated. In the brain, a synapse on the soma can result in very strong memories or emotions.

Excitatory Synapses

Most excitatory synapses in the brain use glutamate or aspartate as the neurotransmitter. These neurotransmitters bind to non-selective cationic channels that allow for Na+ and K+ to pass. Since the driving force for Na+ to move into the cell exceeds the driving force of K+ to leave the cell, these non-selective cationic channels are depolarizing in nature. As mentioned earlier, it takes many EPSPs from these kinds of synapses to depolarize a postsynaptic neuron enough to reach threshold and trigger an action potential.

A very important subset of synapses in the brain includes a group capable of forming memories by increasing the activity and the strength of the synapse. This process is called long-term potentiation. Long-term potentiation operates at the synapse, using the neurotransmitter glutamate and two different classes of receptors, the AMPA and NMDA receptors. The receptor names are derived from their activation by pharmacological agonists. Most glutamate receptors have two temporal components that can be divided into a fast phase and a slow phase. The fast phase is mediated by the AMPA receptor and the slow phase by the NMDA receptor. Upon activation both receptors are permeable to Na+ and K+, but differ in their permeabilities to Ca2+ . The AMPA receptors are activated rapidly and allow very little Ca2+  into the cell. The NMDA receptor is activated much slower but has an increased permeability to Ca2+ .  The Ca2+  ion can increase a plethora of cellular functions, thus controlling the intracellular concentration of Ca2+  is very important. The NMDA receptor is unique in that it is both ligand and voltage regulated. When activated by ligands (glutamate), it becomes permeable to Na+ and K+, but if the charge difference is sufficient, the channel becomes permeable to Ca2+  as well. At resting conditions (-70 mV) the channel pore is clogged by the ion Mg++ and this ion only “pops” out when voltage changes rise to -60 mV. NMDA and AMPA receptors are co-localized together in many synapses. It is possible to stimulate AMPA receptors without stimulating NMDA receptors. However, if enough glutamate is released in the synapse the resultant larger depolarization allows the activation of the NMDA receptor. With the addition of intracellular Ca2+  a second messenger cascade results that can increase the number of glutamate receptors, thereby increasing the strength of the synapse. The change in strength can last for weeks, months, or even years depending on whether or not the synapse is continually used.

Inhibitory Synapses

It may seem somewhat of a paradox to have inhibitory synapses, but the excitability of neurons is essentially governed by a balance between excitation and inhibition. The main inhibitory neurotransmitters are GABA and glycine. Both neurotransmitters bind to receptors that result in an increase conductance of Cl-. Because of the negative charge of Cl- and the fact that it usually moves into the cell, the effect is to oppose depolarization and cause the membrane to move away from threshold.

Modulatory Synapses

Modulatory synapses are those that regulate the excitability of other neurons. Axons associated with modulatory synapses are widespread and diverge throughout the regions of the brain. The function of these modulatory networks is not well understood but it has been demonstrated that some synapses can be "primed" by neuromodulators, so they are able to respond more powerfully to other inputs. An example of a priming neuromodulator is norepinephrine. By itself, norepinephrine has little effect on synaptic transmission, but when a cell is exposed to norepinephrine first, it will react more powerfully to glutamate. In addition, neuromodulatory synapses all involve metabotropic receptors. 

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