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neurophys3,4 spr 2018

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@@ -21,11 +21,11 @@ and electrical...
---
## Electrical and chemical synapses differ in their transmission mechanisms
## Electrical and chemical synapses have different mechanisms for transmission
<div><figcaption class="big">chemical synapse</figcaption><img src="figs/Neuroscience5e-Box-5A-1_c61ef03.jpg" height="200px"><figcaption>Neuroscience Box 5A</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05.01-1R_4f24cb4.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05-01b_5112455.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
<div><figcaption class="big">chemical synapse</figcaption><img src="figs/Neuroscience5e-Box-5A-1_c61ef03.jpg" height="250px"><figcaption>Neuroscience Box 5A</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05.01-1R_4f24cb4.jpg" height="250px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
<div class="fragment fade-in" data-fragment-index="1"><figcaption class="big">electrical synapse</figcaption><img src="figs/Neuroscience5e-Fig-05-01b_5112455.jpg" height="250px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></div>
Note:
@@ -105,6 +105,8 @@ quadrillion synapses, 10^15 in our nervous system
important in diseases of pathological oscillations/synchrony like childhood epilepsy, etc
Electrical synapses and synchronization characterisitc of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
---
## Chemical synapses
@@ -121,43 +123,19 @@ Note:
## Synapse structure as seen by electron microscopy
<div><figcaption class="big">chemical synapse, type 1</figcaption><img src="figs/image2_1bf4990.png" height="200px"><figcaption>[SynapseWeb, Kristen M. Harris, PI](https://synapseweb.clm.utexas.edu)</figcaption></div>
<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="200px"><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="200px"><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="200px"><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>
Note:
* synapse, Gray type 1 is asymmetrical synapse. Usually excitatory synapse. Spherical vesicles.
* synapse, Gray type 2 is symmetrical synapse. Usually inhibitory synapse. Elongated vesicles.
---
## 11 steps of synaptic transmission
<div style="font-size:0.8.em">
<div></div>
1. Neurotransmitter is synthesized and packaged into vesicles
1. An action potential invades the presynaptic terminal
1. Depolarization causes opening of voltage-gated calcium channels
1. There is a rapid influx of Ca²⁺. 1000x concentration difference across the membrane(1x10⁻⁴ mM inside, 1 mM outside)
1. Calcium causes vesicles to fuse with membrane
1. Neurotransmitter is released into cleft
1. Transmitter binds to receptors on postsynaptic cell
1. This opens or closes postsynaptic channels
1. Postsynaptic current flows inside post-synaptic cell
1. Removal of neurotransmitter by glia uptake or enzymatic degradation
1. Retrieval of membrane via endocytosis
</div>
Note:
---
## Synaptic transmission
@@ -169,7 +147,7 @@ Note:
* Action potential in the presynaptic neuron opens voltage-gated Ca²⁺ channels
* Ca²⁺ influx raises [Ca²⁺]i in the nerve terminal
* Elevated [Ca²⁺]i triggers the fusion of synaptic vesicles to the plasma membrane of the presynaptic neuron and exocytosis
* Elevated [Ca²⁺]i triggers the fusion of synaptic vesicles to the plasma membrane of the presynaptic neuron and exocytosis
* Neurotransmitter is released into the synaptic cleft where it diffuses about
* Neurotransmitter binds to specific receptors in the postsynaptic neuron causing channels in that cell to open or close
* Direct action on ligand gated channels
@@ -177,6 +155,30 @@ Note:
* The neurotransmitter is inactivated and/or removed from the synaptic cleft (active transport into presynaptic neuron or glial cells or both)
* The vesicular membrane is recovered by endocytosis and recycled
---
## 11 steps of synaptic transmission
<div style="font-size:0.8em;">
<div></div>
1. **Neurotransmitter synthesized** and/or packaged into vesicles
1. **Action potential** enters the presynaptic terminal
1. **Voltage-gated calcium channels** open because of depolarization
1. **Calcium influx** occurs rapidly. Ca²⁺ concentration difference is 1000x across the cell membrane
1. **Vesicles fuse** with membrane because of calcium flux
1. **Neurotransmitter release** into synaptic cleft
1. **Neuroransmitter binds** to receptors on postsynaptic cell
1. **Postsynaptic ion channels** open or close
1. **Postsynaptic current** flux occurs across post-synaptic cell membrane
1. **Neurotransmitter removed** from synaptic cleft by enzymatic degradation or glial cell uptake
1. **Vesicle membrane** recycled via endocytosis
</div>
Note:
---
@@ -220,6 +222,8 @@ The vagus nerve supplies motor parasympathetic fibers to all the organs except t
Note:
Otto Loewi, 1921
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.
--
@@ -242,14 +246,14 @@ Note:
## Acetylcholine (ACh) shown to be the vagus factor
<div style="font-size:0.8em;">
<div></div>
* 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):
<div style="font-size:0.7em;">
<div></div>
>"for their discoveries relating to chemical transmission of nerve impulses"
</div>
@@ -319,7 +323,7 @@ Note:
How have we come to learn about the properties of chemical synaptic transmission?
---
<!--
## Neuromuscular junction
@@ -327,11 +331,9 @@ How have we come to learn about the properties of chemical synaptic transmission
<div><img src="figs/image11_5a29be3.png" height="200px"><figcaption></figcaption></div>
Note:
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.
---
## Muscle action potentials
@@ -341,11 +343,6 @@ motor unit is a motor neuron’s axon terminals and all the skeletal muscle fibe
<figure><img src="figs/endplate-muscle-AP_copy_3914f33.jpg" height="200px"><figcaption></figcaption></figure>
Note:
--
## Muscle action potentials
* Recordings in the junction reveal local potential changes at the end plate before a regenerative action potential is produced
@@ -353,27 +350,20 @@ Note:
<figure><img src="figs/endplate-potential-muscle-AP_copy_3befd61.jpg" height="200px"><figcaption></figcaption></figure>
Note:
--
## Muscle action potentials
* These local potentials are called end plate potentials (EPPs)
* End plate potentials are generated **at the end plate**
<figure><img src="figs/endplate-potential-muscle-AP-curare_copy_6afd350.jpg" height="200px"><figcaption></figcaption></figure>
Note:
-->
---
## End plate potential
A presynaptic action potential releases a lot of ACh, opening channels in the muscle cell. The resulting depolarization is called an end plate potential (EPP).
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).
<div><img src="figs/Neuroscience5e-Fig-05.06-1R_copy_c01be61.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></div>
@@ -382,7 +372,13 @@ A presynaptic action potential releases a lot of ACh, opening channels in the mu
Note:
End plate potentials evoked by motor neuron stimulation almost are almost always above threshold and result in an action potential along the muscle fiber
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.
---
@@ -413,11 +409,20 @@ Note:
## Quantal neurotransmission
* By lowering Ca²⁺ one can reduce the amount of transmitter released by an AP
* Here [Ca²⁺] is so low that *many* presynaptic APs fail to release any ACh
* Other APs release 1 to 6 quanta
<div style="width:350px; float:left; font-size:0.7em;">
<div></div>
<figure><img src="figs/Neuroscience5e-Fig-05.07-1R_copy_dd645da.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.7</figcaption></figure>
* Lowering [Ca²⁺] reduces the amount of total transmitter (no. of vesicles) released by an AP
* Here [Ca²⁺] is so low that *often* presynaptic APs fail to release any ACh. But sometimes APs will release 1 to 6 quanta
* The distribution of stimulated EPPs in low [Ca²⁺] has multiple modes (several local maxima). Multiples of the smallest EPP amplitude (e.g. 0.4 mV)
</div>
<figure style="width:550px; margin:0 25px; float:left;">
<figcaption class="big">Histogram of EPP amplitudes in low [Ca<sup>2+</sup>]</figcaption>
<img src="figs/Neuroscience5e-Fig-05.07-1R_copy_dd645da.jpg" height="400px">
<figcaption>Neuroscience 5e Fig. 5.7</figcaption>
</figure>
Note:
@@ -432,7 +437,7 @@ If you measure the amplitudes of these small low calcium EPPs and plot their dis
* 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
* Bernard Katz Nobel prize (1970)
* Bernard Katz, Nobel prize (1970)
<figure><img src="figs/image12_0957581.png" height="100px"><figcaption>Bernard Katz</figcaption></figure>
@@ -503,9 +508,9 @@ Note:
--
## The role of Ca²⁺
## The role of calcium
<div style="font-size:0.8em; margin:25px 0;">
<div style="width: 400px; float:left; font-size:0.7em;">
<div></div>
* If extracellular Ca²⁺ is removed or Ca²⁺ entry is blocked, there will be no release
@@ -513,7 +518,14 @@ Note:
</div>
<div><figcaption class="big">Voltage-clamp presynaptic neuron and block Na⁺/K⁺ currents with TTX/TEA</figcaption><img src="figs/Neuroscience5e-Fig-05.10-0_copy_a76faf6.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.10</figcaption></div>
<div style="width: 450px; float:left; margin: 0 25px">
<figcaption class="big">
Voltage-clamp presynaptic neuron and
block Na⁺/K⁺ currents with TTX/TEA
</figcaption>
<img src="figs/Neuroscience5e-Fig-05.10-0_copy_a76faf6.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.10</figcaption></div>
Note:
@@ -523,9 +535,9 @@ Note:
--
## The role of Ca²⁺
## The role of calcium
<div style="font-size:0.8em; margin:25px 0;">
<div style="font-size:0.7em; margin:25px 0;">
<div></div>
* Intracellular injection of Ca²⁺ into the presynaptic terminal will stimulate release
@@ -533,8 +545,9 @@ Note:
</div>
<div><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><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>
<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>
Note:
@@ -548,7 +561,7 @@ Note:
---
## There are lots of proteins involved in synaptic vesicle cycling
## Many proteins are involved in synaptic vesicle cycling
* 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
@@ -583,7 +596,7 @@ Model after Takamori et al 2006
Note:
NSF: ATPase NSF important for fusion of vesicle with membranes of the golgi apparatus. NEM senstivie fusion protein.
NSF: ATPase NSF important for fusion of vesicle with membranes of the golgi apparatus. NEM sensitive fusion protein.
snaps: soluble NSF-attachment proteins
@@ -595,17 +608,26 @@ Model after Takamori et al 2006
## Molecular mechanisms of synaptic vesicle exocytosis
* SNAP-25 is a plasma membrane SNARE that regulates the assembly of two other SNAREs
* Syntaxin is a plasma membrane SNARE
* Synaptobrevin is a vesicle SNARE
* Together they tether the vesicle to the plasma membrane
<div style="width: 400px; float:left; font-size:0.7em">
<div></div>
* SNARES ('SNAP' receptors) tether the vesicle to plasma membrane
* SNAP-25 is a plasma membrane SNARE that regulates the assembly of two other SNAREs
* Syntaxin is a plasma membrane SNARE
* Synaptobrevin is a vesicle SNARE
* Synaptotagmin is a vesicle Ca²⁺ sensor and helps trigger vesicle fusion
<figure><figcaption class="big">Vesicle bound to plasma membrane</figcaption><img src="figs/Neuroscience5e-Fig-05.14-1R_copy_6de21e5.jpg" height="200px"><figcaption>Neuroscience 5e Fig. 5.14</figcaption></figure>
</div>
<div style="width: 450px; float:left; margin: 0 25px;"><figcaption class="big">Vesicle bound to plasma membrane</figcaption><img src="figs/Neuroscience5e-Fig-05.14-1R_copy_6de21e5.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.14</figcaption></div>
Note:
Many proteins specific to presynaptic terminals have been isolated.
These proteins are required for different steps of vesicle cycling: budding, docking, priming, fusion.
NSF
: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus)
: ATPase
@@ -643,9 +665,7 @@ Note:
>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]
---
--
## Synaptic vesicle toxins
@@ -668,7 +688,7 @@ SNARES
---
--
## Botox
@@ -683,6 +703,7 @@ Note:
when botox is injected in small amounts, it can effectively weaken a muscle for a period of three to four months
---
## Synaptic transmission summary video
@@ -693,14 +714,9 @@ Note:
---
## Midterm thursday
## Midterm tuesday
* Similar format as the practice midterm
* 100 points total, 25% of your grade.
* 100 points total, 25% of your grade
* Covers material in lectures 1–6
* today's material covers Chapter 5, pages 77-95
* Hannah's office hrs this week: Wednesday 3:30 – 5:30pm Biomed 101
Note:
---
* James' extra office hrs this week: Friday 1:30 – 3:30pm Biomed 101