neurophys4

neurophysiology4.md

@@ -3,7 +3,11 @@
 * Synapses– functional contacts between neurons
 * 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
+* Electrical– **direct** flow of current between neurons
+
+<div style="font-size:0.5em;">
+<!-- date: -->
+</div>
 
 
 Note:
@@ -36,17 +40,19 @@ Note:
 ## Electrical synapses
 
 * Less common than chemical synapses
-* The cell membranes of two cells are linked together via gap junctions
-* Current flows **directly** from one neuron to another via gap junctions– form large pores between cells made up of connexin proteins
+* The cell membranes of two cells are linked together via **gap junctions**
+* Current flows **directly** from one neuron to another via gap junctions– form large pores (compared to ion channels) between cells made up of connexin proteins
 * The signal is very fast– the only limit is diffusion
 * Signals can go in both directions
-* Are used to synchronize electrical activity among populations of neurons
+* Function to **synchronize** electrical activity among populations of neurons
 
 Note:
 
+We have a quadrillion synapses, 10^15 in our nervous system. A tiny fraction are electrical synapses.
+
 These electrical synapse or gap junction synapses are thought to be more common among inhibitory interneurons in the brain—
 
-quadrillion synapses, 10^15 in our nervous system
+Pore is approx 1 nm in diameter. Allows passage of small molecular weight substances like intracellular metabolites (a few hundred daltons), but not proteins (typically 5-500 kilodaltons in diameter)
 
 ---
 
@@ -60,35 +66,26 @@ Note:
 
 * connexins— extracellular loops and disulfide bridges
 * 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
+   - versus 20-40nm separation at a chemical synaptic cleft
+* passive ionic current flow, small substances like ATP and second messengers can pass through
 
 
 <!-- <img src="figs/image1_e4cc3f1.png" height="300px"> -->
 
-Current in the presynaptic cell is not felt directly by post-synaptic cell for a chemical synapse.
-
---
-
-## Electrical synapses
-
-<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>
+In contrast to gap junctions/electrical synapses, for chemical synapses current flow does not occur directly from the presynaptic cell to postsynaptic cell. 
 
 
-Note:
+gap junction proteins:
+connexins (chordates), innexins (invertebrates), and also pannexins. Similar topologies but dissimilar gene/amino acid sequences. 
 
-In Crayfish an action potential in one neuron spreads quickly to the next in fraction of a millisecond.
+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]. Cx36 KO mouse has no obvious behavioral phenotype other than retinal deficits[^Connors:2004].
 
---
+50% of mammalian connexins widely expressed in CNS. Some strong in astrocytes (Cx26,30,43) or oligodendrocytes (Cx29,32,47) [^Connors:2004]
 
-## Electrical synapses
+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.
 
-<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>
+c elegans: 959 total cells in adult hermaphrodite. 302 are neurons, 58 are glia. Every cell in worm expresses 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.
 
-Note:
-
-In hippocampal neurons gap junctions can make neurons fire in synchrony
 
 ---
 
@@ -103,40 +100,28 @@ In hippocampal neurons gap junctions can make neurons fire in synchrony
 
 Note:
 
-quadrillion synapses, 10^15 in our nervous system
+Electrical synapses could play an important role in diseases of pathological oscillations/synchrony like childhood epilepsy.
 
-important in diseases of pathological oscillations/synchrony like childhood epilepsy, etc
+Electrical synapses and synchronization of activity is characteristic of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
 
-Electrical synapses and synchronization characterisitc of cells that stimulate pulses of pituitary hormones (e.g oxytocin/vasopressin secretion).
+Important for neuronal networks in the pons, medulla: nucleus ambiguous, pre-botzinger complex, solitary nucleus
 
-medulla and pons, medulla: nucleus ambiguous, pre-botzinger complex, solitary nucleus
+Inferior olivary nucleus: source of climbing fiber input to cerebellar cortex. ultrastructure and electrophysiology (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 evidence between neurons. 2-8Hz synchronous oscillations. [^Connors:2004]
 
-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 electrical coupling (cells 40 um apart). [^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]
 
-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.
 
-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.
+The retina has widespread electrical coupling. Extensive between the amacrine cells (interneurons) that synthesize GABA, acetylcholine as neurotransmitter), 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.
+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
 
@@ -144,17 +129,38 @@ 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].
+## Electrical synapses
+
+<figure> 
+<figcaption class="big">Synchronous spikes between two crayfish neurons</figcaption>
+<img src="figs/Neuroscience5e-Fig-05.02-1R_copy_2f541cc.jpg" height="400px"><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 can spread quickly to the next in fraction of a millisecond.
+
+--
+
+## Electrical synapses
+
+<figure>
+<figcaption class="big">Synchronous spikes between a pair of mammalian hippocampal neurons</figcaption>
+<img src="figs/Neuroscience5e-Fig-05.02-2R_copy_3cd5bb0.jpg" height="400px"><figcaption>Neuroscience 6e Fig. 5.3, 5e Fig. 5.2; from Beierlein et al. 2000 </figcaption></figure>
+
+Note:
+
+In hippocampal neurons, gap junctions can make neurons fire in synchrony
 
-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.
 
 ---
 
 ## Chemical synapses
 
-* The majority of connections use chemical synapses
-* They form at the synaptic cleft
+* Majority of connections use chemical synapses
+* Form at the synaptic cleft
 * Presynaptic cells have synaptic vesicles that have neurotransmitters in them
 * Post-synaptic cells have neurotransmitter receptors on the plasma membrane
 
@@ -165,13 +171,21 @@ Note:
 
 ## Synapse structure as seen by electron microscopy
 
-<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 1</figcaption><img src="figs/image2_1bf4990.png" height="220px"><figcaption>
 
-<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>
+[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">chemical synapse, type 2</figcaption><img src="figs/image3_5af29bc.png" height="220px"><figcaption>
 
-<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>
+[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>
 
 Note:
 
@@ -235,11 +249,19 @@ Note:
 
 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.
+Vagus nerve (/ˈveɪɡəs/ vay-gəs)  
+: responsible for many things  
+: heart rate, gastrointestinal peristalsis, sweating, and some muscle movements in the mouth, including speech (via the recurrent laryngeal nerve)  
+: supplies motor parasympathetic fibers to all organs except the supra-renal (adrenal) glands, from the neck down to the second segment colon   
+: historically called the pneumogastric nerve  
+: is the tenth cranial nerve
+: regulates parasympathetic control of the heart and digestive tract  
+: vagus nerves are paired but often referred as singular  
+: has some afferent fibers that innervate the inner portion of the outer ear  
+: afferent fibers in vagus nerve innervating the pharynx, responsible for gag reflex  
 
-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:
+vagus nerve 
+skeletal muscles controlled by vagus nerve include:
 
 * Cricothyroid muscle
 * Levator veli palatini muscle
@@ -249,12 +271,6 @@ The vagus nerve supplies motor parasympathetic fibers to all the organs except t
 * 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.*
-
 
 ---
 
@@ -270,7 +286,7 @@ 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.
+This figure no longer is in 6e of textbook.
 
 --
 
@@ -305,11 +321,10 @@ Note:
 
 Note:
 
-
-* 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
+  -  Curare used as a paralyzing poison by South American indigenous peoples for hunting that causes respiratory asphixiation (diaphragm muscle paralysis) in prey  
+  - Curare is a plant alkaloid that is a competitive and reversible inhibitors of nicotinic acetylcholine receptor (nAChR)
+
 
 ---
 
@@ -454,7 +469,7 @@ Note:
 * 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.
+This work was on frog neuromuscular junc in 1950s but subsequent investigations have demonstrated these synaptic properties for all chemical synapses studied to date.
 
 ---
 
@@ -483,6 +498,9 @@ If you measure the amplitudes of these small low calcium EPPs and plot their dis
 
 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) 
 
+quantum, quanta (wn, noun)  
+: ((physics) the smallest discrete quantity of some physical property that a system can possess (according to quantum theory))  
+
 ---
 
 ## Quantal neurotransmission
@@ -516,10 +534,10 @@ Note:
 * All that vesicle fusion– why doesn’t the membrane keep growing and growing?
 * Synaptic vesicle membranes get recycled quickly
 * Are endocytosed in clathrin coated vesicles which fuse to endosome and bud off again
-* Can use a pulse chase experiment to show this
 
 Note:
 
+Can use a pulse chase experiment to show this -->
 
 
 --
@@ -530,8 +548,8 @@ Note:
 
 
 Note:
-
-(Experiments by Heuser and Reese, 1973). HRP enzyme forms dense reaction product, can be visualized easily in electron microscopy.
+ 
+Pulse chase 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.
 
@@ -558,6 +576,7 @@ Note:
 
 Note:
 
+Calcium flux is essential for chemical synaptic neurotransmission.
 
 
 --
@@ -584,7 +603,7 @@ block Na⁺/K⁺ currents with TTX/TEA
 
 Note:
 
-(Augustine and Eckert 1984)
+experiment done in giant squid (Augustine and Eckert 1984)
 
 
 --
@@ -611,7 +630,7 @@ Note:
 
 *Fluorescent dye that binds calcium (Smith et al 1993)*
 
-*squid giant axon from contacts the contractile muscular mantle responsible for water expulsion and squid jet propulsion*
+*squid giant axon contacts the contractile muscular mantle responsible for water expulsion and squid jet propulsion*
 
 ---
 
@@ -720,21 +739,33 @@ Model based on crystal structure work for SNAP25 from Sutton 1998, Madej 2014, Z
 
 Note:
 
-[from https://en.wikipedia.org/wiki/Botulinum_toxin:](https://en.wikipedia.org/wiki/Botulinum_toxin:)
+* cleavage of SNARE proteins inhibits acetylcholine release
+* botulinum toxins specifically cleave SNAREs, preventing synaptic vesicles from docking and fusing with plasma membrane
+* blocking release of acetylcholine results in flaccid paralysis of muscles (typical of botulism)
+* [https://en.wikipedia.org/wiki/Botulinum_toxin](https://en.wikipedia.org/wiki/Botulinum_toxin)
 
->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 cleaves the synaptobrevin SNARE protein within spinal cord interneurons. This results in less inhibition of spinal cord motor neurons giving rise to muscle hyperexcitation and "tetanic" contractions 
+
+Thus two definitions for tetanus from wordnet, one referring to the bacterial toxin and one referring to a hyperexcitable phenotype in muscle tissue:
+
+tetanus (wn, noun)  
+: an acute and serious infection of the central nervous system caused by bacterial infection of open wounds; spasms of the jaw and laryngeal muscles may occur during the late stages  
+: a sustained muscular contraction resulting from a rapid series of nerve impulses  
+
+Thus in animal physiology when discussing sustained excitation of muscle tissue, it may be referred as "tetanic" stimulation or a muscle "in tetanus".. even when there is no tetanus toxin.
 
 --
 
 ## Synaptic vesicle toxins
 
-Tetanus toxin and various types of botulinum toxin act by preventing exocytosis.
+Tetanus toxin and botulinum toxins act by cleave synaptic SNARE proteins, 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, see also Clinical Application 6e p. 99-100</figcaption></figure>
 
 
 Note:
 
+Tetanus toxin and botulinum toxins are all from *Clostridium* bacteria. 
 
 <!-- ## Botox
 
@@ -743,8 +774,6 @@ Note:
 
 <figure><img src="figs/photo_botox_behandlung_a000d47.jpeg" height="200px"><figcaption></figcaption></figure>
 
-
-
 when botox is injected in small amounts, it can effectively weaken a muscle for a period of three to four months
  -->
 
@@ -757,11 +786,3 @@ when botox is injected in small amounts, it can effectively weaken a muscle for
 
 Note:
 
-<!--
-## Midterm thursday
-
-* Similar format as the practice midterm
-* 100 points total, 25% of your grade
-* Covers material in lectures 1–6
-
- -->