* Two general classes– chemical and electrical synapses
* Chemical– neurons talk to each other by release of neurotransmitters
* Electrical– direct, passive flow of current between neurons
Note:
Thus far we’ve discussed how neurons generate action potentials that propagate down axons with high fidelity over cm’s to to meters of space and the ion channels in the membrane that underly voltage dependent excitability.
But is through synapses that neurons actually talk with one another and it is also through synapses that the nervous system effects behavior function enabling us to interact with the world around us– in other words there are synapses between pairs of neurons that form the basis of inter-neuronal communication as well as synapses on muscle fibers that neurons use to get our muscles to contract.
Now there are two general classes of synapses, chemical...
Current in the presynaptic cell is not felt directly by post-synaptic cell for a chemical synapse.
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## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
Note:
In Crayfish an action potential in one neuron spreads quickly to the next
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## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
Note:
In hippocampal neurons gap junctions can make neurons fire in synchrony
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## Electrical Synapses: putative functions
* Synchronization of the electrical activity of large populations of neurons
* the large populations of neurosecretory neurons that synthesize and release biologically active peptide neurotransmitters and hormones are extensively connected by electrical synapses
<div><figcaption class="big">chemical synapse, type 1</figcaption><img src="figs/image2_1bf4990.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">chemical synapse, type 2</figcaption><img src="figs/image3_5af29bc.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic vesicles</figcaption><img src="figs/image4_b39a9f7.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<div><figcaption class="big">synaptic cleft</figcaption><img src="figs/image5_a67adf4.png" height="220px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
## The discovery of the neurotransmitter acetylcholine
* Otto Loewi– wanted to figure out how stimulation of vagus nerve caused the heart to slow down
* Vagus nerve (cranial nerve X) has both sensory and motor axons. Regulates heartbeat
* Loewi transfered a solution generated from one heart to slow down another heart even without stimulation
* Demonstrated a diffusible substance was released upon stimulation
Note:
The vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve). It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges.
The vagus nerve (/ˈveɪɡəs/ vay-gəs), historically cited as the pneumogastric nerve, is the tenth cranial nerve or CN X, and interfaces with parasympathetic control of the heart and digestive tract. The vagus nerves are paired; however, they are normally referred to in the singular.
The vagus nerve supplies motor parasympathetic fibers to all the organs except the suprarenal (adrenal) glands, from the neck down to the second segment of the transverse colon. The vagus also controls a few skeletal muscles, notable ones being:
* Cricothyroid muscle
* Levator veli palatini muscle
* Salpingopharyngeus muscle
* Palatoglossus muscle
* Palatopharyngeus muscle
* Superior, middle and inferior pharyngeal constrictors
* Muscles of the larynx (speech).
*This means that the vagus nerve is responsible for such varied tasks as heart rate, gastrointestinal peristalsis, sweating, and quite a few muscle movements in the mouth, including speech (via the recurrent laryngeal nerve).*
*It also has some afferent fibers that innervate the inner (canal) portion of the outer ear (via the auricular branch, also known as Alderman's nerve) and part of the meninges. This explains why a person may cough when tickled on the ear, such as when trying to remove ear wax with a cotton swab.[citation needed]*
*Afferent vagus nerve fibers innervating the pharynx and back of the throat are responsible for the gag reflex.*
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## The discovery of acetylcholine
<div><img src="figs/Neuroscience5e-Fig-05.04-1R_copy_a5a415a.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.4</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><img src="figs/Neuroscience5e-Fig-05.04-2R_copy_87d0da2.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.4</figcaption></div>
Free acetylcholine acts on **muscarinic receptors** which **hyperpolarize** the cells of the SA node and slow the conduction of the action potential through the AV node. This slows heart rate. Acetylcholine also decreases Ca2+ influx which lowers the heart's force of contraction.
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## The discovery of acetylcholine
<div style="font-size:0.7em;">
<div></div>
Otto Loewi (Austrian)– on the discovery of vagus nerve substance:
>"In the night of Easter Saturday, 1921, I awoke, turned on the light, and jotted down a few notes on a tiny slip of paper. Then I fell asleep again. It occurred to me at six o'clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. That Sunday was the most desperate day in my whole scientific life. During the next night, however, I awoke again, at three o'clock, and I remembered what it was. This time I did not take any risk; I got up immediately, went to the laboratory, made the experiment on the frog's heart, described above, and at five o' clock the chemical transmission of nervous impulse was conclusively proved."
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Note:
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## Acetylcholine (ACh) shown to be the vagus factor
* Sir Henry Dale purified ACh (1914) and showed that it is vagus nerve substance
* Can apply ACh to muscle and evoke an end plate potential (EPP)
* ACh action has same pharmacology as vagus nerve substance in that it is sensitive to curare (a plant poison that kills by preventing muscle contraction). Competes with curare for receptor binding
* Henry Dale and Otto Loewi shared Nobel prize (1936):
>"for their discoveries relating to chemical transmission of nerve impulses"
</div>
Note:
*Curare was used as a paralyzing poison by South American indigenous people. The prey was shot by arrows or blowgun darts dipped in curare, leading to asphyxiation owing to the inability of the victim's respiratory muscles to contract.*
*Curare /kʊˈrɑːri/[1] or /kjʊˈrɑːri/[2] is a common name for various plant extract alkaloid arrow poisons originating from Central and South America. These poisons function by competitively and reversibly inhibiting the nicotinic acetylcholine receptor (nAChR), which is a subtype of acetylcholine receptor found at the neuromuscular junction. This causes weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm.*
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## Formal criteria that define a neurotransmitter
1. Must be present in the presynaptic neuron
2. Must be released in response to a depolarization and be Ca²⁺ dependent
3. Must have specific receptors localized on the post-synaptic cell
* Note– It does not have to function uniquely as a neurotransmitter (it may have other functions). e.g. glutamate, glycine, ATP
Note:
There are a few criteria that define a neurotransmitter...
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## Criteria that define a neurotransmitter
<div><figcaption class="big">present in presynaptic cell</figcaption><img src="figs/Neuroscience5e-Box-05A-0R-1_copy_bd28d1f.jpg" height="400px"><figcaption>Neuroscience 5e Box 5A</figcaption></div>
It depends on how you count, but maybe 30 - 100 different molecule types, with 10 of them doing 99% of the work. More than 100 different neurotransmitters have been identified.
There are two main broad categories of neurotransmitters: "Small molecule" neurotransmitters (glutamate, GABA, acetylcholine, biogenic amines (dopamine, serotonin, noradrenaline, and histamine)) and neuropeptides (opioid peptides, substance P). ATP/purines and unsaturated fatty acids like endocannabinoids (anandamide, 2-AG) also can act as neurotransmitters.
motor unit is a motor neuron’s axon terminals and all the skeletal muscle fibers it innervates (10 for extraocular muscles, 1000 for thigh muscles). Motor pool is a bunch of motor units of same fiber type.
A presynaptic action potential releases a lot of ACh, opening channels in the muscle cell. The resulting depolarization in the muscle cell at the neuromuscular junction is called an end plate potential (EPP).
Muscle fibers are excitable cells. They are multinucleated myocytes. They too generate action potentials.
End plate potentials evoked by motor neuron stimulation almost are almost always above threshold and result in an action potential along the muscle fiber.
It is the synaptic potential at the neuromuscular junction.
motor unit is a motor neuron’s axon terminals and all the skeletal muscle fibers it innervates (10 for extraocular muscles, 1000 for thigh muscles). Motor pool is a bunch of motor units of same fiber type.
* Spontaneous changes in potential even in the absence of an action potential
* Same shape as EPPs but smaller (1 mV vs 50+ mV)
* Sensitive to agents that block ACh receptors
* Removing Ca²⁺ from media reduces EPPs to MEPPs
* Thus EPPs are a bunch of MEPPs added up
Note:
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## Comparison of MEPPs and subthreshold EPPs
<figure><img src="figs/Neuroscience5e-Fig-05.06-2Rc_copy_864df54.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></figure>
Note:
* in the absence of stimulation there is spontaneous postsynaptic membrane transients called minature EPPs. Small amplitude.
* Bath in low calcium and stimulate you get small subthreshold EPPs that are about the same size as the MEPPs.
* Examination of the muscle membrane potential at high gain reveals small, spontaneous depolarizations. These are miniature end plate potentials (MEPPs)
If you measure the amplitudes of these small low calcium EPPs and plot their distribution, e.g. this histogram here you can see a certain statistical distribution that indicates these amplitudes fall into discrete steps or quanta showing that the smallest amplitude ones that are about the same size as the spontaneous MEPPs must be result of neurotransmitter release from single synaptic vesicles.
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## Quantal neurotransmission
* The **MEPP is the quantal event of neurotransmission**. It represents the postsynaptic response to the release of a single vesicle of neurotransmitter
* The EPP is the result of the synchronized release of many vesicles. It is the sum of many MEPPs
<div style="width:400px; float:left"><figcaption class="big">microinjection of Ca²⁺ into presynaptic terminal</figcaption><img src="figs/Neuroscience5e-Fig-05.11-2R_copy_13a54e8.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.11</figcaption></div>
<div style="width:450px; float:left; margin: 0 25px"><figcaption class="big">microinjection of Ca²⁺ chelator BAPTA into presynaptic terminal</figcaption><img src="figs/Neuroscience5e-Fig-05.11-3R_copy_6d4bfd9.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.11</figcaption></div>
* Many specific proteins have been isolated from presynaptic terminals
* Some of these proteins are required for different steps of vesicle cycling: budding, docking, priming, fusion
Note:
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## We know a lot about the proteins involved in vesicle fusion
* Yeast genetics and biochemistry have defined proteins involved in general vesicle fusion (SEC proteins).
* Homologues in synaptic vesicles
* Proteins have been found that are required in specific steps of fusion: budding, docking, priming, fusion.
-->
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## Presynaptic proteins implicated in synaptic vesicle cycling
<figure><figcaption class="big">Molecular model of a synaptic vesicle</figcaption><img src="figs/Neuroscience5e-Fig-05.13-1R_copy_f29479f.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.13</figcaption></figure>
Note:
Model after Takamori et al 2006
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## Presynaptic proteins implicated in synaptic vesicle cycling
<figure><figcaption class="big">The vesicle trafficking cycle</figcaption><img src="figs/Neuroscience5e-Fig-05.13-2R_copy_464b425.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.13</figcaption></figure>
>Cleavage of the SNARE proteins inhibits release of acetylcholine.[45] Hence, botulinum toxins A, B, and E specifically cleave SNAREs, preventing "neurosecretory vesicles" from docking/fusing with the interior surface of the plasma membrane of the nerve synapse, and so block release of neurotransmitter. In inhibiting acetylcholine release, nerve impulses are blocked, causing the flaccid (sagging) paralysis of muscles characteristic of botulism[45]
Tetanus toxin and various types of botulinum toxin act by preventing exocytosis.
<figure><figcaption class="big">SNARE protein sites cleaved by tetanus and botulinum toxins</figcaption><img src="figs/Neuroscience5e-Box-05B-2-0_copy_0d09c20.jpg" height="400px"><figcaption>Neuroscience 5e Box 5B</figcaption></figure>
Note:
NSF
: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus)
* Dermatologists have been using botulinum toxin (or Botox) for cosmetic purposes
* When injected locally into a particular muscle or surrounding area, Botox causes a paralysis of that muscle due to a blockade of ACh release from the incoming motor nerve fibers. This leads to a reduction of wrinkle lines, although effective for only a few months
