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BIOLOGY 2C03 (138)
Kim Dej (45)

Neuron I

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Kim Dej

Neuro Midterm Review Introduction to the Neuron I. Morphology: a. Neurons contain machinery for extremely active protein synthesis and packing, like liver and pancreas cells. (Ribosomes in ER, Golgi complex, mitochondria). b. Microtubules (of α and β tubulin and microtubule associated proteins [MAPs]) are important for maintaining the shape. i. Microtubules help transport vesicles and organelles to the axon terminals via anterograde transport (kinesin motor), and bring stuff back via retrograde transport (dynein motors). c. Neurofilaments, neuronal intermediate filaments, are responsible for axon diameter. d. 99% of cytoplasm is in the axon. e. Stacks of rough ER are called Nissl bodies in neurons. f. Synapses onto the cell body itself are more often inhibitory, and very powerful. g. Dendrites: i. Dendritic fields allow neurons to selectively sample incoming messages. ii. Most dendrites give off dendritic spines. The spines are areas of chemical isolation. iii. Usually excitatory synapses at the spines, and local changes in ion concentration aren’t diluted by the whole dendrite, so spines remember what’s happened to them for a long time. h. Axons: i. Single axon from each neuron, with integration of synaptic potentials occurring at the axon hillock. + ii. Very high density of voltage-gated Na channels here. iii. Axon collaterals are usually modulatory in nature. iv. On average a single neuron gives off 1000’s of axon terminals. II. Ion Channels: a. All ion channels allow either positively OR negatively charged ions. b. Channels can be ligand- or voltage-gated, but can also bind molecules (usually cyclic nucleotides) on the inner surface of the neuron to hold them open or keep them closed. c. Great majority of cation channels exclude Ca and allow Na or K . + + III. Synapses: + a. A.P. hits the axon terminal, and the depolarization from voltage-gated Na channels causes the opening of Ca channels, which causes fusion of synaptic vesicles and presynaptic membrane. b. Tetrodotoxin (TTX) blocks voltage-gated Na channels, TEA blocks K channels. Even with both these blocked, you can cause N.T. release from the synapse by direct stimulation. c. There are dendro-dendritic synapses that release n.t. even w/o an A.P. d. Axo-axonic synapses can produce presynaptic inhibition by opening K channels. 2+ e. Ca is the key b/c removing external Ca or blocking Ca channels inhibits N.T. release, you can see Ca flowing into terminals during N.T. release, and injecting Ca evokes or augments N.T. release. i. Ca may interact directly with the vesicles or presynaptic membrane, via an effector like calmodulin. ii. We discovered N.T. was stored in vesicles b/c its release is quantal, not continuously graded. f. Post-synaptic receptors are most often ionotropic. i. Acetylcholine is the transmitter of neuromuscular junctions. It opens a channel permeable to both Na and K in the postsynaptic membrane, which has an E orevbout 0 mV, so it depolarizes. ii. Excitation is produced if the reversal potential is above the spike firing threshold and inhibition if it’s below. It is NOT a factor of whether E is rev more negative or positive than resting! 1. You can have inhibitory depolarizations, therefore! g. Another large group of receptors activate GTP-binding proteins (G-proteins), and are also called metabotropic receptors. i. Slower-acting b/c they activate 2 messengers, but stronger and longer- lasting. h. The location of the synapse is very important, b/c of λ. Axosomatic synapses are generally more powerful than axo-dendritic or axo-spinous. i. Most inhibitory synapses are on the cell bodies while most excitatory synapses are on dendrites and spines, b/c the driving force for Cl is zero- when the neuron is at -70 mV, so is most effective at the final segment. i. Gap Junctions are formed by connexins combining to make connexons. i. Largely confined to depolarizing signals, and are very simple. Conduction of Decremental and Regenerative Signals I. Cable properties of neurons are passive properties, flow w/o channels. a. Time constant (τ) and length constant (λ) take into account membrane resistance, axoplasm (internal) resistance, and the thinness of the membrane. b. As diameter goes down resistance goes up and λ gets smaller. a. λ = sqroot (r /rm i b. r i R/πri, and r = Rm/2πr. m c. τ is the amount of time it takes to get to about 60% of starting value, so if you + make 5 mV of Na enter it’ll take 10 ms for the neuron to be depolarized by 3 mV, so τ = 10 ms. τ = RC, where R = internal resistance and C = capacitance. ii. Capacitance is the build-up of stored charge, and the thinner the separa-x/λ, the higher the capacitance. d. ΔV = Δx e , so ΔV falls off exponentially with distance from the source. II. Ion stuff and Nernst Equation a. Standard membrane potential is -70 mV. + b. Na equilibrium potential is +64 mV c. K+ equilibrium potential is -86 mV. d. Cl- equilibrium potential is -78 mV. 2+ e. Ca equilibrium potential is +116 mV. iii. Because this is more negative than the AP threshold, Cl- channels are therefore inhibitory. j. For monovalent ions, E ion= 58 mV log(K /K).o i k. I ion (VionE m, wheiong is conductance. l. WEIGHTED NERNST EQUATION: i. E rev (g Na )KE )Na E K / (gNag K + 1 ii. So the reversal potential depends on the conductance of the channel to both ions and the equilibrium potential of them both. m. Dendrites don’t have the same positive feedback loop b/c they don’t have enough voltage-gated Na channels. e. Excitatory synapses far from the hillock will produce small depolarizations, inputs on large-caliber dendrites have more of an effect, and inputs must be triggered with appropriate delays to sum together. f. Myelin both increases the length constant and reduces the time constant, by increasing membrane resistance and decreasing C. g. Action Potentials: a. Total current flow across a membrane is I total gNaV -Em) +Na (V kE )m k i. The minimum V wherm I totalecomes inward is the threshold. b. A.P.s are terminated by voltage-gated Na channels becoming inactivated after a few ms, and delayed rectifier K channels driving V back even m closer to Ekthan at rest. Refractory period. c. Studying the squid giant axon and either removing external Na or blocking K channels with TEA allowed them to identify that the initial inward current is Na and the delayed outward is K. d. The increased density of Na channels in the axon allows propagation. e. Conduction velocity of axons ranges between 0.5-150 m/sec. h. Take homes: a. Conduction of signals in dendrites is graded and decremental, while conduction in axons is regenerative and all-or-none. b. Passive spread of current is a factor in the speed of both dendritic and axonal transmission, with the caliber of the process the biggest determinant. Glial Cells of the CNS and PNS I. Astrocytes: a. Facts: i. Most numerous glial cells, outnumbering neurons 10:1. + ii. Inexcitable, high resting conductance to K , R.P. of -90 mV. 1. Essentially only permeable to K . + 2. May allow them to remove K released during activity and redistribute it, preventing extracellular accumulation. 3. Their gap junctions allow them to form a syncytium, so they can move ions and metabolites between cells. 4. Bergmann glial cells perform the roles of astrocytes in the cerebellum, and Müller glial cells do it in the retina. b. During development, they secrete growth factors, guide neuronal migration, and enhance synapse formation. c. Remove ions and neurotransmitters that accumulate extracellularly. i. They contain glutamine synthetase so they can convert glutamate to glutamine, and the glutamate transporter GLAST/EAAT1. ii. They send out processes that ensheath synapses, and these glutamate transporters help remove glutamate from the extracellular space after excitatory transmission, preventing excitotoxicity. iii. It’s possible that the elevation of extracellular K and decrease of Na accompanying brain ischemia leads to reversed cycling in these transmitters and actually contributes to neuronal death. iv. Patients with ALS have decreased EAAT2 in the ventral spinal cord, possibly accelerating the death of alpha motor neurons here. v. Glutamate causes oscillations of intracellular calcium in astrocytes, which can be propagated as a calcium wave that increases the excitability of surrounding neurons through release of ATP or glut. vi. These Ca waves may also help synchronize groups of neurons through release of glutamate, and control dilation of brain vessels via production and release of arachidonic acid to smooth muscle. d. Provide neurons with energy. i. Have aggregations of glycogen granules. e. Astrocytes play a central role in brain water homeostasis. i. They have lots of the water channel aquaporin-4 in their endfeet, which allows them to take up ions and neurotransmitters and then have water move in via osmosis. f. Exhibit contact spacing, with little or no overlap. i. Express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP) in their primary processes, making them star-shaped and providing structural support to brain tissue. 1. These processes extend to contact capillaries at end feet. Glucose is transported from blood at the endfeet by glucose transporters and either used, released (as glucose or lactate via glycolysis), or stored. g. Disease: i. Alexander Disease consists of cytoplasmic inclusions called Rosenthal fibers (GFAP and small stress proteins) accumulating in astrocytes and leading to issues early in life and typically death before age 10. Results from gain in function mutations in GFAP. ii. Damage to the brain can lead to reactive astrocytosis, which includes increased expression of GFAP and possible development of astroglial scars. iii. Astrocytes can release angiogenic factors, which may be involved in glioblastomas. II. Microglial Cells: III. Schwann Cells: a. Myelin-producing cells of the PNS. i. Myelin divides axons into internodes, paranodes, and nodes of Ranvier. ii. Na channels are clustered in the initial segment and nodes of Ranvier. b. Include satellite cells around the sensory neurons in the DRG, autonomic neurons, and around the giant complexes in the enteric nervous system. i. Have a basal lamina over their outer surface isolating the neuron from the surrounding “collagenous world”. c. Ensheathing Schwann cells surround non-myelinated axons. i. Regular, low level of renewal by local proliferation. ii. Can wrap multiple cells. d. Myelinating Schwann cells provide a sheath of 100-150 concentric lamellae from 1-1.5mm, with Schwann cells that surround many axons early in development eventually only surrounding a single axon. i. Caliber of axon determines whether it signals Schwann cell to make myelin or not. ii. Myelinating Schwann cells normally never reenter cell cycle. iii. Myelination begins by the inner lip of the Schwann cell lengthening and the cell nucleus rotating around the axon, pushing the inner loop around. The spiraled lamellae fuse to form major dense lines, while the membrane faces that can be traced to a potential connection to the extracellular fluid form the intraperiod lines. 1. Innermost lamellae contain the “oldest” constituents. e. Disease: i. If the original myelin sheath is damaged, the Schwann cell reenters the cell cycle, amputates its old myelin sheath, and several daughter cells compete for sites to remyelinate the original axon, generally resulting in shorter myelin sheaths. ii. Guillain-Barré syndrome includes autoimmune attacks on myelin-forming Schwann cells. iii. If an axon has degenerated and new regenerating axons are formed, daughter Schwann cells provide support for the axonal outgrowth. iv. Charcot-Marie-Tooth Disease: 1. Distal wasting, high arches and hammer toes, weakness and clawed hands b/c of degeneration of motor neurons. 2. Caused by constant de- and attempts at re-myelination, resulting in “onion cells” where multiple Schwann cells rae trying to wrap. Symptoms occur when the axon dies and you just have the empty onion bulbs. IV. Oligodendrocytes: a. The myelin-producing cells of the CNS. b. Oligodendrocytes are capable of myelinating many axons. c. Biochemical composition of CNS myelin is somewhat different from peripheral. d. Oligodendrocytes are capable of proliferation and remyelination after injuries, but are much less effective than Schwann cells Development I. Overall: a. At day 25 the brain’s just a tube of rapidly proliferating cells. b. At day 35 flexures develop and post-mitotic neurons migrate away. c. At day 100 the cerebral cortex has begun to cover the rest of the brain. d. By day 210 or so sulci and gyri develop. e. We have proliferation, migration and aggregation, differentiation, axon growth, synapse formation, and regressive events. II. Proliferation: a. Shortly after gastrulation has taken place and we have our trilaminar germ disc, dorsal ectodermal cells become rapidly proliferating neuro-ectoderm, while ventral cells become slowly dividing skin. b. Henson’s node or the blastopore lip is at the invagination of mesoderm and endoderm, and contains tissue that leads to the production of nervous tissue, as shown by transplantation experiments. i. Transplantation leads to the generation of a second neural tube from ectoderm that would have become skin otherwise. c. The Default Model says ectoderm, if left alone, will become neuro-ectoderm that will produce neurons and glia. i. BMP-4, produced by lateral mesoderm and endoderm, prods overlying ectoderm away from the default into an epithelial path. ii. Molecules secreted by the mesodermal notochord, including noggin, follistatin, and chordin, prevent BMPs from triggering an intracellular cascade and keep ectoderm committed neurally. d. As the quickly-proliferating neural ectoderm builds up it forms the neural plate at the midline, which begins to apply mechanical pressure to the surrounding neuroectoderm and producing neural folds, which eventually fold over the neural groove to form the neural tube. i. The neural tube produces all of the neurons and most of the glia of the CNS. ii. Microglia are of mesodermal origin, arising from cells that migrate into the developing CNS from the blood. iii. Folic acid encourages closure of neural tube a few weeks in. e. Left behind as the tube closes are neural crests, which develop into all neurons and supporting cells of the PNS. i. Neural crest cells go dorsally to become melanocytes or ventrally to become neurons and supporting cells. Many different cells come from a single progenitor population! f. Neuroblasts attach to both the inner and outer surfaces of the neural tube, with the nuclei synthesizing DNA near the pial surface of the ventricular zone during S phase and migrating during the G phases of mitosis. Just before dividing, the neuroblast breaks attachment with the outer surface and divides in the ventricular zone. i. Both daughter cells can re-enter mitosis (early), both can permanently differentiate (late), or one may re-enter and one migrate (intermediate). g. For the most part, in both the neural crests and neural tube progenitor cells generate neurons early and supporting cells later. i. The exception are radial cells, which initially support but retain the ability to generate both neurons and glia late in development. 1. Radial glia can undergo asymmetric division to give rise to one radial glia and one neuronal progenitor. After all neurons are produced, the radial glial cell appears to transform into an astrocyte precursor. ii. In the neural tube, glioblasts quickly change into oligodendrocyte- and astrocyte precursor cells. Secretion of trophic factors by astrocytes keeps the OPCs mitotically active! iii. Notch is a transmembrane receptor expressed in the ventricular zone. 1. Activation of Notch signaling leads to a reduction in the number of neurons and increase in number of radial glia. 2. Delta is one ligand for Notch. When Notch is activated, nuclear protein RBP-JHairy/Enhancer of Split (HES) bHLH proteins that negatively regulate proneural bHLH factors. h. For the vast majority of CNS neurons, after the end of the 2 trimester proliferation ends forever. In some areas mitosis ends much earlier. III. Migration: a. Radial glia guide cells leaving mitosis to migrate away from proliferative zones. b. Spinal cord formation: i. Earliest cells move up to just beneath the marginal zone, while later-born cells move up but not past these. So the neurons on the inside are youngest, in an outside-in pattern of formation. ii. Cells begin to cluster into a dorsal alar plate and a ventral basal plate, separated by the sulcus limitans. iii. Cells in the spinal cord are told to become either one of four kinds of interneurons or motor neurons, with the ventralmost interneurons and ventrally located motor neurons forming a team to generate and execute patterns of movement. iv. Sonic hedgehog is secreted first by cells of the ventrally-located notochord, thus existing as a gradient from dorsal to ventral. v. Notocord Shh in turn induces a second zone of Shh in the ventrally-located floor plate. 1. Receptors for Shh have differing affinities and different effects, so as the concentration of Shh varies from ventral to dorsal so does the -/-ect. -/- 2. Shh and Gli3 double mutants have a restored pathway of dorsal- ventral differentiation, suggesting Gli genes are signal transducers in the Shh pathway. vi. The marginal zone, which initially had only processes of mitotic cells from the ventricular zone, remains free of cell bodies throughout life. 1. As axons grow between the spinal cord and the brain, the marginal zone therefore becomes white matter, with different sections invaded by specific groups of axons. vii. Neurons of like types express the same members of the cadherin family, which causes them to aggregate together within the spinal cord. c. Cerebral Cortex Migration: i. Unlike in the spinal cord, proliferation does not only occur in the ventricular zone. The subventricular zone develops to take up generation of excitatory neurons and supporting cells, which travel radially. ii. Inhibitory neurons arise from the lateral and medial ganglionic eminences, together with neurons of the basal ganglia. These have to migrate laterally to reach the cortex 1. Because basal ganglia neurons are predominantly GABAergic, it’s like the cortex raided this source to get its inhibitory neurons, which make up 1/5 of its neurons. iii. The 1 -born neurons of the cortex form the preplate in the intermediate zone, which then sends off a band of very large Cajal-retzius cells into the marginal zone and inner bands of small neurons that remain in the intermediate zone as the subplate. iv. Neurons born later on migrate to the area between the subplate neurons and the Cajal-retzius cells to form the cortical plate. v. The cortical plate is composed of post- mitotic and migratory cells that quickly mature to form distinct layers of cells, with subsequent generations of cells migrating PAST the oldest ones (layer 6) so that the youngest cells (layer 2) are right next to layer 1, whose Cajal-Retzius cells die and leave layer 1 with few neurons. This is an inside-out pattern of migration. 1. Cells along a particular information path are all daughters of the same mother cell. 2. This allows information processing in stages in the cortex and the retina, with those stages specific by an early pattern of neural generation and migration. 3. This is why unlike in the spinal cord, gray matter of the cortex is on the outside with the axon-containing white matter on the inside. 4. Cajal-Retzius cells are crucial for the inside-out pattern of migration because they secrete reelin, which greases the wheels and allows younger cells to sneak out towards the marginal zone. a. Mutations in reelin either invert the order of neurons or lead to lissencephaly (smooth cortex), and lots of intellectual and behavioral problems.\ b. Some patients with lissencephaly have mutations in the gene Lis1. c. Female patients with mutations in DCX have “double cortex” (mosaic), while male patients have lissencephaly, since it’s X-linked. d. Regionalizaton in the Brain: i. Very early in development we get basic divisions: ii. Prosencephalon: Divides into telencephalon and diencephalon. iii. Mesencephalon: iv. Rhombencephalon: Divides into metencephalon and caudal myelencephalon. 1. Rhombencephalon is aided by dividing into rhombomeres, with repulsive ephrins in one population and ephrin receptors in a neighboring population. 2. These, and whatever serves as rhombomeres in the prosencephalon, are examples of location playing a role in specifying neuronal development and function. Axon Guidance and Neuronal Regeneration I. Plasticity: a. If you cut a frog’s optic nerve and rotate the eye, the original targets are re- innervated, but there’s no orientation compensation by the CNS. b. This suggests a fixed set of cues directs connections in the visual system. c. If you remove a part of the retina, you see expansion of the retinal map on the tectum. If you remove a portion of the tectum, you see a compression of the map. d. Ablation of neurons that contribute to a certain pathway results in inability of their connecting neurons to extend that direction—they don’t fasciculate with any other axon pathways close by, and just stall. II. Guidance clues for commissural axons during development: a. Repellants from the dorsal spinal cord, directing them ventrally. i. Morphogens like BMP made at the dorsal midline repel axons from the dorsal spinal cord. b. Attractive cues from the ventral spinal cord pulling them ventrally. i. Netrin receptors are members of the DCC and UNC5 family. 1. Conserved axonal attractants, pull commissural interneurons ventrally towards the floor plate. 2. Without netrin-1 axons lose their way if perturbed. 3. If neurons express DCC on their surface, Netrin is an attractant. 4. If neurons express BOTH DCC and UNC5, they view Netrin as a repellant! a. Inhibition via a PKA inhibitor also converts Netrin to a repellant. ii. Shh made by floor plate cells attracts commissural axons in collaboration with Netrin-1. c. Repulsive cues from the ventral spinal cord, facilitating mid-line crossing and preventing re-crossing. i. Slits go to Robos. ii. A Slit gradient gives a “bump” to the commissural axons to get them to cross the CNS midline and not remain stuck due to netrin attraction. 1. As the axons grow ventrally, they are insensitive to Slit even though they have Robo1 and Robo2, because they also have Robo3, which suppresses activity of 1 and 2. As soon as they cross the midline, though, Robo3 is downregulated and they are repulsed from the midline. 2. People with mutations in Robo3 have Horizontal Gaze Palsy and Progressive Scoliosis because they have aberrant axon guidance during development. d. Attractants that guide post-crossing commissural axons anteriorly towards their targets in the brain. i. After midline crossing, commissural axons are also attracted rostrally/anteriorly by a decreasing gradient of Wnt protein. ii. Cortical spinal tract axons extending caudally in the dorsal spinal cord are repelled caudally by a high rostral to low caudal gradient of Wnts 1 and 5. e. Other axon guiding cues: i. Semaphorin receptors are the Plexins and Neuropilins. 1. Semaphorins are potent repellants, keeping neurons constrained from entering areas they shouldn’t be. ii. Ephrins go to EphA and EphBs – repellants! f. Contact cues: i. Cell adhesion molecules (CAMs) help sculpt neuronal trajectories. 1. Ig superfamily members counter repulsive cues to maintain a balance of attraction and repulsion. 2. Ig superfamily members like Fasciclin II (FasII) are required to keep axons that make up fascicles close to one another. a. If FasII is over-expressed in all motor neurons, motor axons fail to defasciculate and bypass their normal choice points. This is the same result as if there is a LOF mutation in Sem-1a and you don’t have its repulsion. b. A double Sema-1a and FasII LOF mutant restores balance! 3. Ig superfamily members can also signal repulsion. 4. Dscam is required for repulsive interactions allowing individual neurons to distinguish self from non-self. a. In drosophila, individual neurons lacking Dscam generate branches that fail to separate from one another and instead extend within the same lobe, or do not correctly spread out their arborizations. b. In vertebrates, Dscam appears to be required for generating well separated axonal arborizations in the retina. III. Neuronal growth cone morphology and dynamics: a. Composed of filopodia, lamellipodia, peripheral and central domains. b. Constant state of flux, extending and retracting processes. c. Growth cone advances by protruding, adhering, moving, de-adhering, and steering in response to directional cues. d. Cytoskeletal organization and growth dynamics: i. Actin filaments are present in peripheral or cortical cytoplasm of axons and dendrites. 1. Filopodia extend and retract through regulation of rates of actin polymerization and depolymerization as monomers are added and removed in response to ATP hydrolysis. 2. By inhibiting retrograde actin flow via myosin motors, lamella protrude. Extracellular receptors can do this! 3. Cytochalasin B inhibits aactin polymerization and leads to cessation of filopodial protrusion. 4. Myosin 1 inhibitors stop retrograde flow but not filopodial protrusion. 5. Slit/RobosrGAP (inactivates Cdc42)retraction 6. Sema4d/PlexinB-->PDZ-RHO-GEF (Activates rho)retraction. 7. Activate RacPromote outgrowth. ii. Larger microtubules with heterodimeric subunits, have plus and minus ends, with elongation at the plus end. 1. Present within axon with the plus end pointing away from the soma. 2. If we block MT dynamic instability we have no directed axon outgrowth, but still have filopodial protrusion. 3. Slit activates CLASP, which stabilizes microtubules and prevents their extension into the growth cone. 4. NGF-mediated neurite outgrowth  promotion of microtubule assembly. iii. Intermediate filaments stabilize axons and define process caliber. IV. Neuronal regeneration: a. In the periphery, damage makes Schwann cells provide permissive factors (including trophic support) and macrophages quickly remove debris and myelin. b. In the CNS, environmental inhibitory cues are not removed, and there aren’t growth factors released. Both are targets for CNS regeneration. c. Peripheral nerve grafts overcome CNS inhibition. d. CNS myelin inhibits growth unless you use monoclonal antibodies against it. e. We can see some regeneration in brain stem lesions following treatment with IN- 1 blocking antibodies, as well as dramatic collateral sprouting. IN-1 is a major contributor to inhibition. f. NOGO has a domain which mimics the inhibitory effects of CNS myelin. i. Antagonistic NOGO peptides and some NOGO receptor (NGR) peptides will block their interaction, and are potential agents for promoting neuronal regeneration! ii. The NGF receptor p75 may be the common signal transducer, with activation of p75activation of Rhopromotion of inhibition. g. MAG, an Ig superfamily member, is an inhibitor of DRG outgrowth for older neurons but an attractant until early potnatal time! i. It and other bifunctional cues are probably modulated by cyclic nucleotides. h. So we can overcome CNS inhibition by: i. Blocking NOGO, MAG, or other myelin inhibitors. ii. Blocking semaphorins, ephrins, slits, or other repulsive guidance cues. iii. Inhibiting downstream effectors of repulsive guidance like Rho. iv. Also have to overcome repulsive components of glial scars, including semaphorins. v. Also have to provide neuronal growth factors like neurotrophins, or activate receptor systems for permissive growth, including integrins and ECM components. Cell Death During Development and Synapse Formation I. Overview: a. About a 75% neuronal survival rate through human gestation. b. Cells die to match neuron and target cell populations, as error correction, to generate sexually dimorphic regions of the nervous system, and to get rid of cells with a transient function. II. What factors influence neuronal survival? a. Much pruning occurs around when neurons innervate their target tissue, and if we ablate or transplant target tissues we can see missing or extra motor neurons. b. Neurotrophic factors are released in limiting amounts, so only neurons that succeed in competing for them survive. c. There are also neurotrophic factors from additional sources (glia, etc.) that influence the overall neurotrophic state of a cell. i. Target-derived, ECM-derived, pathway-derived, glial-derived, afferent- derived, hormonal, etc. III. Non-neuronal cells also die. a. Oligodendrocyte overproduction and subsequent death may occur to match the number of oligodendrocytes to the amount of surface area to be myelinated. IV. How do they die? a. Cells undergo apoptosis, influenced by signals from the environment received in the context of their state of maturity. b. Nuclei degenerate, apoptotic bodies appear, proteins cross-link, BOOM. c. Cell death promoters including Bax 1, Bak, Bik, and Bad act to inhibit cell death inhibitors, which include Bcl-2, Bcl-XL, Bcl-W. If the cell death inhibitors aren’t working, then Apaf-1 can activate caspases1-14, which cause cell death through the intrinsic or mitochondrial pathway. V. Families of neuronal growth factors: a. Neurotrophins (including NGF), FGFs, IGFs, EGFs, PDGFs, Cytokines, and TGFβs. VI. NGF: a. Functions at least in part as a target-derived NGF. b. Rescues neurons that would otherwise die in development. c. Mice overexpressing NGF in skin have more sympathetic neurons. d. Anti-NGF antibodies leads to loss of sympathetic neurons. e. Death of sensory and sympathetic neurons following axotomy can be prevented by systemic NGF administration! f. All about 120 a.a.’s in length, basic, function as homodimers. g. NGF receptors: i. TrkA is the receptor for NGF and TrkB & C are the receptors for others in its family. ii. The Trk family are receptor tyrosine kinases, with B and C widely expressed throughout the brain but TrkA localized to only a few types of neurons. iii. NGF induces dimerization and transphosphorylation of TrkA on multiple tyrosine residues. This increases the catalytic activity of the receptor and provides “docking sites” for PID- and SH-2 domain-containing proteins, which then recruit signal transducing molecules to the membrane, activating Bcl-2 to prevent death and transcription factors for genes promoting cell growth. iv. The signal from NGF receptors must be retrogradely propogated to the soma. v. One mutation in TrkA can lead to absence of A-delta or C fibers, and Congential Insensitivity to Pain. VII. Synaptogenesis: a. 3 main steps for motorneuron Ach synapse: i. Agrin from the motor neuron strengthens and maintains subsynaptic receptor clustering by minding LRP4 ii. Clustering is mediated by MUSK and rapsyn. iii. Extrasynaptic expression of Ach receptors is repressed. b. So both translocation and transcriptional regulation of receptors are involved. VIII. Modification of Synaptic Connections by Electrical Activity: a. Synapse elimination takes place when presynaptic neurons die, or when a single presynaptic neuron loses some of the cells it innervated. b. At birth, each myotube is innervated by multiple motoneurons. Eventually, it’s only innervated by one. c. It’s possible that the most efficient way to generate the precise number of connections for the mature nervous system is to overshoot and then prune. d. Synapse elimination may well result from activity-mediated signals in the postsynaptic cell. i. To survive, a synapse needs to both be active (to protect itself) and send out a “punishment signal” to kill nearby synapses. Monoamine Systems I. To be a neurotransmitter, minimal criteria is: a. Must mimic the actions of an endogenous transmitter—sufficient. b. Must be generated by ________ neurotransmitter? —sufficient c. Must be selectively blocked –necessary d. Doesn’t have to be released vesicularly or by calcium or whatever. II. Acetylcholine: Transmitter of parasympathetic system. a. Muscarine slowed the heart by stimulating the vagus nerve, while atropine blocked the effects of either vagal stimulation or muscarine, indicating they had a common mechanism of action. b. Taking perfusate from a heart undergoing vagal stimulation and applying it to another confirmed the existence of a transmitter. c. Life cycle of Ach: i. Synthesized in a single reaction by choline acetyltransferase, using Acetyl-CoA from the Krebs cycle and choline taken up in the synaptic terminals. ii. Acts on muscarinic or nicotinic receptors. 1. Muscarinic are G-protein-coupled, blocked by atropine. a. Muscarinic mediate Ach’s effect on cardiac muscle! So atropine reverses bradycardia! 2. Nicotinic are ionotropic, blocked by curare. a. Nicotinic receptors mediate Ach’s effect on skeletal muscle!. iii. Subject to hydrolysis by acetylcholinesterase, producing acetic acid and choline, which is taken up by the presynaptic cell. d. Strategies for manipulation: i. Use acetylcholinesterase inhibitors to block degredation and potentiate cholinergic transmission. Myasthenia gravis treatment. 1. Irreversible inihibitors have been used as nerve gas, interfering with transmission from phrenic to diaphragm. 2. Block a particular type of Ach receptor. a. Nicotinic in the adrenal medulla increase catecholamine secretion. b. M1 receptors in exocrine tissues act via the PPI system. c. M2 receptors in the heart are linked by a G-protein that directly opens K channels to slow the heart. d. M3 receptors in the gut increase secretions. III. Norepinephrine/Noradrenaline: Transmitter of sympathetic system: a. Epinephrine is closely related and released by the adrenal medulla. b. Life-cycle of catecholamines: 3 steps, optional 4 in the adrenal medulla. i. L-Tyrosine  L-Dopa via Tyrosine hydroxylase, rate-limiting. ii. L-Dopa Dopamine v
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