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neurophysiology4.md
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@@ -23,9 +23,9 @@ and electrical...
## 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="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>
<div><figcaption class="big">chemical synapse</figcaption><img src="figs/Neuroscience5e-Box-5A-1_c61ef03.jpg" height="250px"><figcaption>Neuroscience 6e 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-05.01-1R_4f24cb4.jpg" height="250px"><figcaption>Neuroscience 6e 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 6e Fig. 5.1</figcaption></div>
Note:
@@ -52,14 +52,14 @@ quadrillion synapses, 10^15 in our nervous system
## Gap junctions allow current to flow from one cell to the next
<figure><img src="figs/Neuroscience5e-Fig-05.01-3R_f7cb5e4.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.1</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.01-3R_f7cb5e4.jpg" height="400px"><figcaption>6e Fig. 5.2</figcaption></figure>
Note:
* connexins— extracellular loops and disulfide bridges
* 3.5nm separating the apposed lipid bilayers connected through connexon hemichannels
* 3.5nm separating the apposed lipid bilayers connected through connexon hemichannels
* 20-40nm separation at a chemical synaptic cleft
* passive ionic current flow, small substance like ATP and second messengers
@@ -73,18 +73,18 @@ Current in the presynaptic cell is not felt directly by post-synaptic cell for a
## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Fushpan and Potter, 1959 </figcaption></figure>
Note:
In Crayfish an action potential in one neuron spreads quickly to the next
In Crayfish an action potential in one neuron spreads quickly to the next in fraction of a millisecond.
--
## Electrical synapses
<figure><img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.2</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Beierlein et al. 2000 </figcaption></figure>
Note:
@@ -109,9 +109,45 @@ important in diseases of pathological oscillations/synchrony like childhood epil
Electrical synapses and synchronization characterisitc of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
medulla and pons, medulla: nucleus ambiguous, pre-botzinger complex, solitay nucleus
medulla and pons, medulla: nucleus ambiguous, pre-botzinger complex, solitary nucleus
connexins (chordates), innexins, pannexins, (invertebrates)
inferior olivary nucleus: source of climbing fiber input to cerebellar cortex. ultastructure adn ephys (Llinas 1974) found electrical coupling between pairs of neurons in cat inferior olive. Same thing demonstrated later in guinea pig, rat, mouse. Also dye coupling. 2-8Hz synchronous oscillasions. [^Connors:2004]
thalamic reticular nucleus (thin interneuron layer) of dorsal thalamus. Spatially localized coupling (cells 40 um apart). [^Connors:2004]
hippocampus. between pyramidal neurons and also interneurons. [^Connors:2004]
in neocortex only rarely found between pyramidal neurons, often between interneurons. 'Late spiking' L1 interneurons make electrical synapse with other neurons of the same class 83% of time but with other interneuron types only 2% of time. Maybe necessary for gamma frequency rhthyms.
retina has widespread electrical coupling. Extensive between amacrine cells, scoptopic vision impaired in Cx36 KO mice from loss in rods and cones and between amacrine cells and bipolar cells.
Cx36 in both olfactory epithelium and olfactory bulb. between granule cells. between mitral cells in same glomerulus.
Early in development, first postnatal week in rat electrical coupling extensive between motor neurons in spinal cord. Declines during first postnatal week but still present in adult.
gap junction proteins:
connexins (chordates), innexins (invertebrates). Similar topologies but dissimilar gene/amino acid sequences. Also pannexins in
connexins : 20 isoforms in humans and mice. 40 connecxin orthologues across species. Cx36 36kDa protein, hexamer possibly only forming hemichannels homotypically, specific to neurons. [^Connors:2004]
50% of mammalian connexins widely expressed in CNS. Some strong in astrocytes (Cx26,30,43) or oligodendrocytes (Cx29,32,47) [^Connors:2004]
gap junctions first found and studied in invertebrates. Innexins for gap junctions in drosophila, c elegans molluscs, annelids, playhelminthes. Mammalian pannexin genes are similar to innexins and Px1 and Px2 mRNA is present in pyramidal neurons and interneurons of the hippocampus.
gap junctions may be sensitive to Ca2+ influx, at least at high concentrations. But are very sensitive to small intracellular (but not extracellular) pH changes and intracellular pH changes occur doing neuronal activity.
[^Connors:2004]: https://www.annualreviews.org/doi/10.1146/annurev.neuro.26.041002.131128
Carbenoxolone (from licorice root) not very specific for Cx36.
Quinine selectively blocks Cx36,50,45. Mefloquine is a derivative that is 100x more potent.
Cx36 KO mouse has no obvious behavioral phenotype other than retinal deficits[^Connors:2004].
c elegans: 959 total cells in adult hermaphrodite. 302 are neurons, 58 are glia. Every cell in worm expresss innexins, most of the 20+ isoforms are expressed in nervous system and every neuron is believed to form gap junctions. 7000 synapses. 6393, 890 electrical junctions. 1410 NMJ.
---
@@ -146,7 +182,7 @@ Note:
## Synaptic transmission
<figure><img src="figs/Neuroscience5e-Fig-05.03-0_copy_9fad940.jpg" height="500px"><figcaption></figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.03-0_copy_9fad940.jpg" height="500px"><figcaption>Neuroscience 6e Fig. 5.4</figcaption></figure>
Note:
@@ -155,15 +191,17 @@ Note:
* 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
* 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
* Indirect action on G-protein coupled channels
* Neurotransmitter binds to specific neurotransmitter receptors in the postsynaptic neuron causing ion channels in that cell to open or close
* 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
neurotransmitter receptors :
* direction action through ligand gated channels
* indirect action through G protein coupled receptors
---
## 11 steps of synaptic transmission
## The steps of synaptic transmission
<div style="font-size:0.8em;">
<div></div>
@@ -232,6 +270,8 @@ 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.
This figure no longer is in 6e.
--
## The discovery of acetylcholine
@@ -257,7 +297,6 @@ Note:
* 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"
@@ -266,9 +305,11 @@ Note:
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.*
* curare used as a paralyzing poison by South American indigenous peoples for hunting that causes respiratory asphixiation (diaphragm muscle paralysis) in prey
* alkaloid arrow poisons that are competitive and reversible inhibitors of nicotinic acetylcholine receptor (nAChR)
* 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
---
@@ -316,6 +357,8 @@ can act at long distances, from the cell body
-->
This box figure also no longer in 6e.
---
## Synaptic transmission is quantal
@@ -327,9 +370,9 @@ can act at long distances, from the cell body
Note:
How have we come to learn about the properties of chemical synaptic transmission?
How have we come to learn about the properties of chemical synaptic transmission?
<!--
<!--
## Neuromuscular junction
@@ -371,9 +414,9 @@ motor unit is a motor neuron’s axon terminals and all the skeletal muscle fibe
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>
<div><img src="figs/Neuroscience5e-Fig-05.06-1R_copy_c01be61.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.5</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-05.06-2Rb_copy_4bf3e7d.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></div>
<div><img src="figs/Neuroscience5e-Fig-05.06-2Rb_copy_4bf3e7d.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.5</figcaption></div>
Note:
@@ -400,17 +443,21 @@ Note:
---
## Comparison of MEPPs and subthreshold EPPs
## Spontaneous MEPPs and subthreshold EPPs evoked in low [Ca2+] have similar amplitudes
<figure><img src="figs/Neuroscience5e-Fig-05.06-2Rc_copy_864df54.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.6</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.06-2Rc_copy_864df54.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.5; from Fatt and Katz *J Physiol* 1952</figcaption></figure>
Note:
0.5mV depolarizations.
* 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)
This work was on frog neuromuscular junc in 1950s but subsequent investigations have demosntrated these synaptic properties for all chemical synapses studied to date.
---
## Quantal neurotransmission
@@ -427,7 +474,7 @@ Note:
<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>
<figcaption>Neuroscience 6e Fig. 5.6; Boyd and Martin *J Physiol* 1955 </figcaption>
</figure>
@@ -436,6 +483,7 @@ Note:
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.
Poisson statistics used to analyse independent occurence of unitary events. Red curve shows what the distribution would expected to be if neurotransmitter release is quantal, made up of discrete message packets (vesicles) made of multiples of MEPP amplitudes (e.g. 0.4 mV)
---
@@ -480,18 +528,20 @@ Note:
## Local recycling of synaptic vesicles in presynaptic terminals
<figure><img src="figs/Neuroscience5e-Fig-05.09-1R_copy_e1bd0b0.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.9</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.09-1R_copy_e1bd0b0.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.8</figcaption></figure>
Note:
(Heuser and Reese, 1973)
(Experiments by Heuser and Reese, 1973). HRP enzyme forms dense reaction product, can be visualized easily in electron microscopy.
Clathrin has a unique three arm structure that forms little geodesic dome coverings around membrane segments and dynamin forms a ring that pinches or 'buds' off the vesicle.
---
## Local recycling of synaptic vesicles in presynaptic terminals
<figure><img src="figs/Neuroscience5e-Fig-05.09-2R_copy_4977b31.jpg" height="300px"><figcaption>Neuroscience 5e Fig. 5.9</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.09-2R_copy_4977b31.jpg" height="300px"><figcaption>Neuroscience 6e Fig. 5.8, 5e Fig. 5.9</figcaption></figure>
@@ -531,7 +581,7 @@ 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>
<img src="figs/Neuroscience5e-Fig-05.10-0_copy_a76faf6.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.9, 5e Fig. 5.10; from Augustine and Eckert *J Physiol* 1984</figcaption></div>
Note:
@@ -551,9 +601,9 @@ Note:
</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: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 6e Fig. 5.10; from Smith et al. *J Physiol* 1993, Miledi *Proc R Sci Lon B* 1973</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>
<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 6e Fig. 5.10; from Adler et al *J Neurosci* 1991</figcaption></div>
Note:
@@ -569,12 +619,24 @@ Note:
## Many proteins are involved in synaptic vesicle cycling
<div style="font-size:0.8em; width: 400px">
<div></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
</div>
<div style="float:left; margin:0 20px"><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; from Takamori *Cell* 2006</figcaption></div>
Note:
<!--
Model after Takamori et al 2006
Don't memorize this.
<!--
## 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).
@@ -586,17 +648,6 @@ Note:
## 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
--
## 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>
@@ -617,15 +668,15 @@ Model after Takamori et al 2006
<div style="width: 400px; float:left; font-size:0.7em">
<div></div>
* SNARES ('SNAP' receptors) tether the vesicle to plasma membrane
* **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
* **Synaptotagmin** is a vesicle Ca²⁺ sensor and helps trigger vesicle fusion
</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>
<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 6e Fig. 5.12; based on Sutton *Nature* 1998, Madej 2014</figcaption></div>
Note:
@@ -634,6 +685,8 @@ Note:
Many proteins specific to presynaptic terminals have been isolated.
These proteins are required for different steps of vesicle cycling: budding, docking, priming, fusion.
Just know there are is a calcium sensitive protein called synaptotagmin and that there are proteins like SNAREs that help dock and pinch membranes together
NSF
: NEM-sensitive fusion protein (orig found to be important for fusion of vesicles with membranes of Golgi apparatus)
: ATPase
@@ -645,17 +698,19 @@ SNARES
: 'SNAP receptors'
Model based on crystal structure work for SNAP25 from Sutton 1998, Madej 2014, Zhou *Nature* 2015
---
## Molecular mechanisms of synaptic vesicle exocytosis
<figure><img src="figs/Neuroscience5e-Fig-05.14-2R_copy_0df493d.jpg" height="400px"><figcaption>Neuroscience 5e Fig. 5.14</figcaption></figure>
<figure><img src="figs/Neuroscience5e-Fig-05.14-2R_copy_0df493d.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.12, 5e Fig. 5.14</figcaption></figure>
Note:
Model based on crystal structure work for SNAP25 from Sutton 1998, Madej 2014, Zhou *Nature* 2015
---
@@ -677,7 +732,7 @@ Note:
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>
<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, see also Clinical Application 6e p. 99-100</figcaption></figure>
Note:
@@ -692,11 +747,7 @@ SNAPs
SNARES
: 'SNAP receptors'
--
## Botox
<!-- ## Botox
* 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
@@ -707,22 +758,22 @@ SNARES
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
<div><video height=400px controls src="figs/Animation05-01SynapticTransmission.mp4"></video><figcaption>Neuroscience 5e Animation 5.1</figcaption></div>
<div><video height=400px controls src="figs/Animation05-01SynapticTransmission_OC.mp4"></video><figcaption>Neuroscience 5e Animation 5.1</figcaption></div>
Note:
---
## Midterm tuesday
<!--
## Midterm thursday
* Similar format as the practice midterm
* 100 points total, 25% of your grade
* Covers material in lectures 1–6
* James' extra office hrs this week: Friday 1:30 – 3:30pm Biomed 101
-->