CSB332 Midterm Review Notes

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Cell and Systems Biology
Francis Bambico

CSB332 Midterm Review Notes - Synapse is made up of o Presynaptic element  Contains synaptic vesicles, which house neurotransmitter that is released after vesicle fusion with the plasma membrane o Synaptic cleft  Gap between presynaptic and postsynaptic elements into which neurotransmitter molecules are released o Postsynaptic element  Contains receptors embedded in the plasma membrane - Different ways by which neurons synapse with each other o Axosomatic synapse = axon synapses onto a cell body o Axodendritic synapse = axon synapses onto a dendritic spine or dendritic shaft o Axoaxonic synapse = axon synapses onto another axon o Capillary = axon synapses onto a capillary o Muscle = axon synapses onto a muscle fiber, called NMJ - Canonical synapse o Presynaptic terminal is in close proximity to the postsynaptic element (1:1) Type 1 synapse Type 2 synapse Asymmetric Symmetric Release glutamate Release GABA Result in an excitatory response in the Result in an inhibitory response in the postsynaptic element postsynaptic element Found on dendritic spines (axodendritic Found on dendritic shafts (axodendritic synapse) and dendritic shafts (?) synapse) and cell bodies (axosomatic synapse) Prominent presynaptic dense projections Less obvious presynaptic dense projections Round synaptic vesicles Flattened synaptic vesicles Large active zone Small active zone (e.g., compartmentalized) Wide synaptic cleft Narrow synaptic cleft Dense basement membrane Modest basement membrane Prominent postsynaptic density Less obvious postsynaptic density - Non-canonical synapse o Presynaptic terminal is not in close proximity to the postsynaptic element o Release other neurotransmitters in massive to reach many postsynaptic targets - Magnetic resonance imaging (MRI) o Produces an anatomical image of the brain o Application of strong magnetic field  Aligns the hydrogen protons in the brain in a parallel/anti-parallel direction  Produces a net longitudinal (north/south) magnetic field vector o Application of radiofrequency (RF) pulse  Disturbs the precession of protons and their alignment  Decreases the net longitudinal magnetic field vector  Produces a horizontal/transverse (east/west) magnetic field vector o Withdrawal of RF pulse  Re-orients the protons towards the longitudinal axis  Re-establishes the peak net longitudinal magnetic field vector  Diminishes the transverse magnetic field vector o T1 relaxation time = the time to recover the peak longitudinal magnetic field vector o T2 relaxation time = the time to diminish the transverse magnetic field vector o Hydrogen protons of gray matter, CSF, white matter, deoxygenated blood, and oxygenated blood have different T1 and T2 relaxation times and will show different intensities of MRI signals - Functional MRI (fMRI) o Produces an image of brain activity by detecting changes in blood flow o Based on the blood oxygen level-dependent (BOLD) signal, which determines how much oxygenated blood gets into different parts of the brain  High oxygenated blood = high brain activity o Generated from the difference between the T2 relaxation times of oxygenated and deoxygenated blood - Diffusion MRI (dMRI) / Diffusion tensor imaging (DTI) o Produces detailed images of axons in white matter o Does not determine the direction of connectivity of these axons - Positron emission tomography (PET) o Positron = anti-matter equivalent of an electron (e.g., anti-electron) o Positron-emitting isotope (e.g., FDG, radioligand) is injected into the carotid artery o PET scanner administers a beam of electrons o Electrons collide with positrons called an annihilation event o Annihilation event emits gamma photons o Gamma photons are detected by a rotating device o High levels of gamma photons = Highly active brain areas = High neuronal firing activity o A person with an anxiety or stress disorder will display high gamma photon readings in the emotional centers of the brain (limbic system) suggesting that neuronal activity in certain limbic areas are abnormally increased in these patients - Behaviour and mental processes required the coordinated communication of groups of neuronal cell bodies (nuclei/ganglia). Each nuclei or ganglia control a specific function or a set of functions (modular organization of the brain). Behaviour and mental processes are carried out by the vast network of synaptic connections of the white matter (connectome). - Subdivisions of the brain o Superior (upper/rostral) structures  Neocortex (or cerebral cortex) controls complex functions (e.g., thinking, problem solving, decision-making, planning, language, attention, abstract reasoning, perception and interpretation of internal and external events, executive function, goal-directed behaviour, personality) o Subcortical structures are beneath the cerebral cortex and around the lateral and third ventricles  Basal ganglia motor complex controls movement and motivation  Caudate nucleus  Lentiform nucleus (putamen + globus pallidus)  Subthalamic nucleus  Substantia nigra  Claustrum  Limbic system controls emotion and memory  Amygdala controls fear response and anxiety  Hippocampus controls memory  Cingulate gyrus regulates mood  Thalamus is the central sensory relay station  Hypothalamus controls motivational and neuroendocrine functions o Inferior (lower/caudal) structures control vital processes and homeostasis  Medulla oblongata controls respiration, heart rate, blood pressure, digestion, swallowing  Spinal cord controls reflex movement - Production of neurotransmitters o Acetylcholine (ACh)  Septal nucleus  Basal nucleus  Motor neurons (neuromuscular junction) o Dopamine  Ventral tegmental area (VTA)  Substantia nigra (SN) o Norepinephrine (NE)  Locus coeruleus (LC) o Serotonin (5-HT)  Raphe nuclei - Structure of the spinal cord (CNS) o Dorsal horn = dorsal (posterior) gray matter of the spinal cord  Substantia gelatinosa interneuron  Dorsal horn ascending commissural interneuron  Axons of dorsal horn interneuron compose the spinothalamic tract  Axon terminals of DRG neuron (afferent) o Ventral horn = ventral gray matter of the spinal cord  Lower motor neuron (efferent) o DRG neuron = cluster of cell bodies that are located outside of the CNS  Pseudo-unipolar type  One axon bifurcates into two branches o Peripheral branch terminates in the pain receptors at the skin (cell body  periphery) o Central branch terminates into the dorsal horn of the spinal cord (cell body  spinal cord) - Simultaneous release of neurotransmitters into a synapse by two or more neurons o DRG neuron releases substance P (SP) and glutamate  binds to and activates the receptors expressed in the cell body of dorsal horn ascending commissural interneurons (also called second order sensory neurons) in the dorsal horn  relays the pain signal to the spinothalamic tract  thalamus  somatosensory cortex  DRG neuron synapses with dorsal horn interneuron o Substantia gelatinosa interneuron releases enkephalin (ENK)  binds to and activates the delta opioid receptors (coupled with inhibitory G proteins) expressed in the axon terminals of DRG neurons  block the entry of calcium into the axon terminal of the DRG neuron  inhibit the release of SP and glutamate from the DRG neuron  Substantia gelatinosa interneuron synapses with DRG neuron  Calcium is important for the maintenance of action potentials  Release of ENK  Activate the opioid receptors expressed in the axon terminals of DRG neurons  Block calcium entry into the presynaptic axon terminal  Decrease the duration of the action potential  Inhibit the release of SP and glutamate  Inhibit the transmission of signals that mediate pain and temperature sensation o Emergency type situations are able to stimulate the substantia gelatinosa interneurons o Other types of neurotransmitters (e.g., norepinephrine) are able to stimulate substantia gelatinosa interneurons - There are 86 billion neurons and 10-50 times more satellite/glial cells in the brain - Types of glial cells o Schwann cells = myelination of axons in the PNS o Oligodendrocytes = myelination of axons in the CNS o Fibrous and protoplasmic astrocytes = make contact with capillaries to form the blood-brain barrier o Ependymal cells = lining the inner brain surface in the ventricles o Microglia = resemble macrophages o Radial glial cells = guide the migration of neurons during development - Electrical functioning of glial cells o Can become depolarized and hyperpolarized o Do not fire action potentials o Contain some voltage-gated Na+ and Ca2+ channels o Contain high quantities of leaky K+ channels  Located in the end feet or the terminal projections of the glial cells  More negative resting membrane potential (up to -95 mV) - Synapses among glial cells o Glial cells communicate with each other via gap junctions (a type of electrical synapse)  Bridge the space between two adjacent glial cells  Connect the cytoplasm of one glial cell to the cytoplasm of another glial cell  Conduction is faster  Current can readily pass from one neuron to another without entering into a synaptic cleft and without getting transduced into chemical signals - Spatial buffering o Potassium is expelled by neurons after depolarization in synaptic clefts o Gap junctions in glial cells regulate potassium concentrations in intracellular clefts via leaky K+ channels  Relay potassium to other areas of the brain that are not active  Prevent abnormal build-up of potassium after neuronal depolarization - Axon growth cone o Responsible for navigation and elongation toward the target o Consists of lamellipodia and filopodia/microspikes  G-actins = monomeric form  F-actin = polymeric form of microfilaments  Microtubule = highly dynamic rope-like polymers of tubulin that maintain cell structure  Located in the central core of the growth cone  Myosin = motor protein moves the microtubule-rich central domain of the growth cone o Stationary phase  Actin filament is not attached to substrate  Actin depolymerization and polymerization is cyclical o Protrusive growth  Actin filament is immobilized by attachment to substrate  Actin polymerization and depolymerization is cyclical  Myosin is able to move the microtubule-rich central domain of the growth cone forward - Axon growth cone guidance and pathfinding o Contact interaction  Cell adhesion molecules (CAM) = membrane-bound glycoproteins  Presynaptic growth cone has to be in physical contact with the postsynaptic cell  Located on the membrane of the developing axon growth cone  Allow minimal movement of the developing axon growth cone  Homophilic interaction (e.g., DCC and DCC, TAG-1 and TAG-1)  Heterophilic interaction (e.g., NrCAM and TAG-1)  Extracellular matrix adhesion molecules (ECM adhesion molecule) = secreted glycoproteins  Presynaptic growth cone has to be in close proximity with the postsynaptic cell  Secreted by glial cells o Short- or long-range attraction or repulsion  Chemotactic molecules = gradients of diffusible extracellular matrix proteins  Secreted by glial cells and neurons  Interacting with CAMs, which are acting as receptors o Example: Commissural interneuron axon growth cone guidance (located in the dorsal horn) (A) Long-range attraction = guides the axon growth cone to travel down (dorsal  ventral) along the midline of the spinal cord  Netrin-1 (chemotactic molecule) = diffusible midline attractant o Secreted by floor plate cells, which are immature glial cells  DCC (CAM) = receptor for netrin-1 o Expressed on the membrane of the axon growth cone (B) Short-range attraction (contact attraction) = guides the axon growth cone laterally to cross the midline of the spinal cord  NrCAM (CAM) = binds to TAG-1 o Expressed on the membrane of floor plate glial cells  TAG-1 (CAM) = binds to NrCAM o Expressed on the membrane of the axon growth cone (C) Short-range repulsion = prevents the axon from re-crossing the midline  Slit (chemotactic molecule) = diffusible midline repellant o Secreted by floor plate glial cells  Robo (CAM) = receptor for Slit o Expressed on the membrane of the axon growth cone  Then there is another set of signaling molecules that guides the commissural interneuron axon growth cone to synapse with neurons in the thalamus o Example: Motor neuron axon growth cone guidance (located in the ventral horn) (A) Long-range repulsion  Slit (chemotactic molecule) + netrin-1 (chemotactic molecule) = spinal cord repellant o Secreted by floor plate glial cells  Unc5 (CAM) = receptor for Slit and Netrin-1 o Expressed on the membrane of the axon growth cone - Synaptogenesis = synapse formation o Involves the differentiation and formation of presynaptic and postsynaptic specializations (e.g., assembly of components) o Example: NMJ synaptogenesis  Motor neuron originates from the ventral horn of the spinal cord and synapses with muscle fiber  Presynaptic and postsynaptic differentiations are triggered by presynaptic and postsynaptic ECM adhesion molecules  Postsynaptic differentiation  Agrin (ECM adhesion molecule) o Different isoforms are produced by the motor neuron and the muscle fiber due to cell-type-specific alternative splicing o Only the isoform that is produced by motor neurons is active during NMJ development  LRP4 = receptor for agrin o Expressed on the membrane of the muscle fiber  Muscle specific kinase (MuSK) = receptor tyrosine kinase = receptor for agrin o Expressed on the membrane of the muscle fiber o Tyrosine kinase = cleave ATP and transfer phosphate group from ATP to another protein (e.g., MuSK, Src, Fyn) o Agrin/MuSK signalling influences postsynaptic gene expression  Accumulation of acetylcholinesterase  Development of basal lamina  Increased concentration and aggregation of ACh receptors  Src and Fyn = intracellular tyrosine kinase o Expressed within the muscle fiber  Rapsyn = intracellular effector of agrin/MuSK signaling o Scaffolds ACh receptors and other postsynaptic proteins into clusters at the synapse and links these to the actin cytoskeleton  Presynaptic differentiation  Laminin-β2 (ECM adhesion molecule) o Released by the muscle fiber in response to agrin/MuSK signaling o Induces presynaptic differentiation  Accumulation of synaptic vesicles  Formation of the active zone  Formation of proteins involved in neurotransmitter release o Example: CNS synaptogenesis  Presynaptic and postsynaptic differentiations are triggered by presynaptic and postsynaptic cell adhesion molecules  Neurexin (CAM)  Expressed on the presynaptic axon growth cone  Induces postsynaptic differentiation o Postsynaptic density (PSD)  Neuroligin (CAM)  Expressed on the postsynaptic neuron membrane  Induces presynaptic differentiation - Synaptogenesis (from 20 weeks until birth) is followed by apoptosis and pruning (from 4 months until 60 years) o Apoptosis = programmed cell death o Pruning via competitive elimination = loss of synapse, retraction of axons, synaptic reorganization  To retain the function of active synapses  To eliminate the non-functional synapses  To fine-tune the connectivity of the neurons and the neuronal circuit - Polyneuronal innervation = many axons innervate a single neuron; unfavourable; must undergo pruning/elimination - Gradients of chemorepulsive proteins guide the topographic target selection of retinal ganglion cells to the optic tectum o Lower forms of mammals (e.g., amphibians, birds, reptiles, frogs)  Do not have primary visual cortex  Visual information is directly relayed to the optic tectum (called superior colliculi in mammals) o Eph A3 = receptor tyrosine kinase  Expressed on the axon terminals of the retinal ganglion cells o Ephrin-A2 and ephrin-A5 = Eph receptor ligands  Expressed on the plasma membrane of the optic tectum cells  Interaction of Eph receptor and ephrin ligand is chemorepulsive o Optic tectum  Anterior tectal neurons = low ephrin-A2 and ephrin-A5 expression  Posterior tectal neurons = high ephrin-A2 and ephrin-A5 expression o Retina  Nasal retinal ganglion cells = low Eph A3 expression  Guided to posterior optic tectum  Temporal retinal ganglion cells = high Eph A3 expression  Guided to anterior optic tectum  Temporal retinal ganglion axons (enriched with Eph A3 receptors) interact in a repulsive manner with posterior tectal neurons (enriched with ephrin ligands), thus driving the axons to synapse with anterior tectal neurons (no expression of ephrin ligands) - Central nervous system (CNS) o Spinal cord o Brain o Optic nerve (1 of the 12 pairs of cranial nerves that project from the brain) - Peripheral nervous system (PNS) o Ganglia = clusters of cell bodies located outside of the CNS (e.g., DRG) o 11 of the 12 pairs of cranial nerves that project from the brain o 31 pairs of spinal nerves that project from the spinal cord - Composition of spinal nerves o Fascicle = bundles of axons from motor (efferent) neurons and sensory (afferent) neurons located outside of the CNS o Perineurium (also called perineurial sheath) = connective tissue that ensheathes fascicles o Endoneurium (also called endoneurial tube, Henle’s sheath, or basal lamina) = connective tissue within the perineurial sheath, includes Schwann cells and delicate reticular (collagenous) fibers around individual axons - Axotomy = nerve injury resulting in the severing of axons (e.g., lesion) o Symptoms  Pain  Fibrillation or fasciculation (muscle twitching, muscle fiber contractions are asynchronous and spontaneous)  Loss of function (motor, sensory, autonomic) and paralysis - Wallerian degeneration = axon degeneration and regeneration changes after axotomy occurring in the CNS and PNS o Response of neurons to nerve injury  Begins 24-36 hours after the lesion  Rapid and robust in the PNS  Slow, incomplete, and less likely to occur in the CNS o Axonal events  Degeneration  Rapid degeneration of the distal axon and the myelin sheath that wraps around it, which leaves behind axonal remnants and myelin debris  Slow degeneration of the proximal axon (e.g., closest to the cell body)  Acute inflammation  Macrophages and microglia invade the site of lesion and phagocytose (clear up) the debris  Regeneration  Schwann cells synthesize BDNF o To maintain the health of the growth cone o To guide the growth cone within the endoneurial tube back to original target  Basal lamina or endoneurial tube must be intact for complete regeneration to take place o Loss of BDNF and NGF  Macrophages de-differentiates (and later re-differentiates) Schwann cells  Schwann cells unable to release cytokines LIF and Reg2  loss of growth factors BDNF and NGF  Muscle fibers and postsynaptic cells synthesize BDNF and NGF  BDNF and NGF unable to bind to receptors on the plasma membrane of the denervated axon terminal  BDNF and NGF unable to be transported into the cell body o Cell body events  Chromatolysis  Injured neurons lose its ability to stain purple/blue with a basophilic staining o Due to degeneration and dispersal of Nissl bodies  Due to loss of BDNF and NGF  Basophilic stain = basic dyes that react with and stain acidic components of the cell (e.g., RNA, DNA, nucleic acids, Nissl bodies = RER + ribosomes) o Hematoxylin stain o Cresyl violet stain (Nissl stain)  Displacement of nucleus  Nucleus will get displaced close to the edge of the cell o Due to loss of BDNF and NGF  Atrophy  Bloating, then shrinking o Due to loss of BDNF and NGF o Presynaptic effect  Retraction of presynaptic axonal inputs  Due to loss of BDNF and NGF - Synthesis and distribution of acetylcholine receptors in the rat neuromuscular junction o Postsynaptic effect  Supersensitivity  Postsynaptic cells (e.g., muscle fibers) become supersensitive to neurotransmitters (e.g., ACh)  Fetal form of muscle fiber + motor neuron axons o Embryonic ACh receptor = 2 βγδ  Shorter half-life compared to the adult form o Expressed along the entire muscle fiber o Starting to concentrate on the motor endplate (postsynaptic region of the NMJ; opposite to the presynaptic axon)  Adult form of muscle fiber + motor neuron axons o Adult ACh receptor = 2 βδε o Concentrated within the ridges of the motor endplate  Adult form of muscle fiber + denervated motor neuron axons o Increased synthesis of embryonic and adult ACh receptors o Increased distribution of embryonic and adult ACh receptors within and outside of the synpase o Results in fibrillation or fasciculation of the muscle fiber  ACh molecule can stimulate embryonic and adult ACh receptors  Increase in ACh receptors (which are Na+ channels in themselves) allow Na+ ions to get inside and cause spontaneous depolarization  Adult form of muscle fiber + denervated motor neuron axons + stimulation/rehabilitation o Decreases the expression of embryonic ACh receptors o Reverts the muscle fiber back into the adult form o Regains the integrity/function of the muscle fiber o Receptor autoradiography = observe the distribution and turnover of ACh receptors  Label the ACh receptor with radioactive α-bungarotxin o In situ hybridization (ISH) = observe the genetic expression/transcription of ACh receptors  Hybridize ACh receptor mRNA with radioactive anti-sense nucleotide probe (complementary to ACh receptor mRNA)  Detect increased/decreased levels of radioactivity o Protein synthesis inhibitors (e.g., actinomyosin, puromycin) = block the appearance of new ACh receptors - Axons of sensory and motor neurons regenerate in the PNS but not in the CNS o Axons of motor (efferent) neurons severed in the CNS do not regrow well o Axons of motor (efferent) neurons severed in the PNS (and cell bodies of motor neurons lie in the spinal cord) can regenerate completely o Axons of sensory (afferent) neurons severed in the PNS can only regenerate in the periphery  E.g., sensory neuronal axons are severed outside of the CNS, so regenerate toward the spinal cord, but stop growing when they reach astrocytic processes at the CNS border - Regeneration in the PNS o Schwann cells  Provide a permissive/supportive environment for axon regeneration  Secrete trophic factors in response to cytokines released by macrophages and microglia o NGF (nerve growth factor) o BDNF (brain-derived neurotrophic factor)  Express cell adhesion molecules  Produce extracellular matrix components o After regeneration has occurred, Schwann cells cease production of these molecules and again ensheath the axon - Regeneration in the CNS o Very limited o More likely in younger people (and animals)  Presence of growth factors, adhesion and guide/chemotactic molecules, nutrients  Therapeutic interventions  Electrical stimulation, elimination of scar tissue, reduction of inflammation  Certain axons can regrow several centimeters and form appropriate synapses o Glial cells (e.g., astrocytes, oligodendrocytes)  Limit axon regeneration  Stop producing pro-growth adhesion molecules (e.g., CAM, ECM adhesion molecules, trophic factors)  Produce growth-inhibiting molecules  Secreted into the extracellular matrix o Chondroitin sulfate proteoglycan (CSPG) o Nitric oxide o Arachidonic acid derivatives  Expressed in adult myelin or oligodendrocyte/astrocyte cell membrane o Nogo-A binding to Nogo-66 receptor on growth cones o Myelin-associated glycoprotein (MAG) o Myelin basic protein (MBP) o Reticulon o Annexins o Semaphorins o Ephrins o Astrocytes  Contribute to the formation of glial scar via gliosis  Prevent the mobility of some regenerating axons (e.g., sensory neuronal axons regenerating toward the spinal cord) - Membrane potential (Vm) o Intrinsic electrical property (or state) of a neuron that is influenced by the external world o Related to the difference in electrical potential between its interior and exterior produced by its interior and chemical (ionic) composition o Able to maintain electrical potential difference o Able to store chemical energy indefinitely  Called potential energy  Measured by a voltmeter o A neuron is a battery, which is a device that can convert stored chemical energy (chemical composition) to kinetic electrical energy (electrical flow) - Electrophysiology o Branch of neurophysiology o Precise measurements of the intrinsic electrical properties of cells (e.g., Vm) -
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