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8/10/2019 Anatomy and Physiology of the Optic Nerve
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1. Anatomy and Physiology1. Anatomy and Physiologyof the Optic Nerveof the Optic Nerve
Alfredo A. Sadun, MD, PhDAlfredo A. Sadun, MD, PhD
Thornton Professor of VisionThornton Professor of Vision
Doheny Eye InstituteDoheny Eye Institute
Departments of Ophthalmology andDepartments of Ophthalmology andNeurosurgeryNeurosurgery
Keck/USC School of MedicineKeck/USC School of Medicine
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Optic Nerve and AnteriorOptic Nerve and Anterior
Visual PathwaysVisual Pathways
AnatomyAnatomy
PhysiologyPhysiology
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RETINARETINA
9 Layers9 Layers
Anatomical layout (horizontalAnatomical layout (horizontal rapheraphe))
33 functional layersfunctional layers
Photoreceptors (rods and cones)Photoreceptors (rods and cones) Bipolar cells andBipolar cells and integratorsintegrators
Retinal ganglion cellsRetinal ganglion cells
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Original Ramon Y Cajal from Golgi stain
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RETINAL LAYERS
NFL
RGC
IPL
INL
OPL
ONL
IS
OS
RPE
SCLERA
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Why Visual Fields respect Horizontal Raphe:
Cogan, trypsin digest
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Lesions of the optic disc/nerveLesions of the optic disc/nerve
Visual field defect =Visual field defect = arcuatearcuate/central/central
Less than 50% loss no effect on:Less than 50% loss no effect on:
VFVF
VAVA
ContrastContrast
ColorColor Disc appearanceDisc appearance
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1B. Neuro1B. Neuro--retinaretina
((NeuroprotectionNeuroprotection and Apoptosis)and Apoptosis)
Alfredo A. Sadun, MD, PhDAlfredo A. Sadun, MD, PhD
Thornton Professor of VisionThornton Professor of Vision
Doheny Eye InstituteDoheny Eye Institute
Departments of Ophthalmology andDepartments of Ophthalmology andNeurosurgeryNeurosurgery
Keck/USC School of MedicineKeck/USC School of Medicine
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Why Visual Fields respect Horizontal Raphe:
Cogan, trypsin digest
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IfIf NeuroprotectionNeuroprotection = good for= good for
neurons then:neurons then:
Wearing a bicycle helmet isWearing a bicycle helmet isneuroprotectionneuroprotection
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DEATH
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Poor Signaling : Black sail sentPoor Signaling : Black sail sent
AgeusAgeus leaping to his deathleaping to his death
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RGCsRGCs = Neurons= Neurons
Die from a variety of processesDie from a variety of processes
NecrosisNecrosisChromotolysisChromotolysis (cellular breakdown)(cellular breakdown)
Membrane disruptionMembrane disruption
Swelling of peripheralSwelling of peripheral cytosolcytosolNoxious to adjacent cellsNoxious to adjacent cells
Release of glutamateRelease of glutamate
Inflammatory changesInflammatory changesApoptosisApoptosis
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APOPTOSISAPOPTOSIS
Cell suicideCell suicideProgrammed cell deathProgrammed cell death
Energy dependentEnergy dependent
Orchestrated series ofOrchestrated series of
intraintra--cellular eventscellular events
Involution of cell/quietInvolution of cell/quietdeathdeath
Sparing of collateralSparing of collateral
damagedamage
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APOPTOSISAPOPTOSIS
WhatWhats so good about it?s so good about it?
OntogenyOntogeny
Tumor controlTumor controlNeuronal specificityNeuronal specificity
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Mitochondria againMitochondria again
Once free living bacteriaOnce free living bacteria
LynnLynn MargulisMargulis model of synergymodel of synergyIncorporation of ATP factoriesIncorporation of ATP factories
Also a built in TIME BOMBAlso a built in TIME BOMB
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How do retinalHow do retinal
ganglion cells die?ganglion cells die?
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Extra cellularExtra cellular
SignalingSignaling
FASFAS--LigandLigand
TNFTNF
Death domainDeath domain
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MitochondrialMitochondrial
Key lynchKey lynch
--pinpin
Membrane pot.Membrane pot.
affected byaffected by
ROSROS BAXBAX
Stabilized byStabilized by
BCLBCL--22
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Open poresOpen pores
Cytochrome CCytochrome C
releasedreleased
Nuclear gene controlNuclear gene control PP--53 promotes53 promotes
PP--35 blocks35 blocks
ReleaseRelease
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Mechanisms of RGC deathMechanisms of RGC death
IschemiaIschemiaCytotoxicCytotoxic (NMDA)(NMDA)
InflammatoryInflammatory
ProPro--inflammatoryinflammatory
Energy depletionEnergy depletion
ROSROSAxonal compromiseAxonal compromise
AxoplasmicAxoplasmic flowflow
Retrograde degenerationRetrograde degeneration
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AIDS OPTIC NERVEAIDS OPTIC NERVE
Degenerated axonsDegenerated axonsLong standingLong standing
Myelination of debrisMyelination of debris
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AIDS OPTICAIDS OPTIC
NERVENERVE
Axonal deg.Axonal deg.
Various stagesVarious stages
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AIDS OPTIC NERVEAIDS OPTIC NERVE
MacrophageMacrophage
Toxic expression?Toxic expression?
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CYTOKINESCYTOKINES
That can induce apoptosisThat can induce apoptosis TNFTNF
ILIL--11
ILIL--2b2b ILIL--66
IFNIFN--gg
That may mitigate apoptosisThat may mitigate apoptosis
ILIL--1010
NGFNGF
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TNF BINDING TO TNF R1TNF BINDING TO TNF R1Liberation of G proteinsLiberation of G proteins
Causing release ofCausing release of phospholipasesphospholipases
Stimulating the release ofStimulating the release of arachadonicarachadonic a.a.
Elaboration of proteinElaboration of protein kinaseskinasesSecondarily activatingSecondarily activating xanthinexanthine oxidaseoxidase
And reactive oxygen species (ROS)And reactive oxygen species (ROS)
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OPTIC NEUROPATHIESOPTIC NEUROPATHIESHow does glaucoma killHow does glaucoma kill RGCsRGCs??
PressurePressure
IschemiaIschemia
NeurotrophicNeurotrophic factorsfactors
M A I
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Mitochondrial Apoptotic Index
Disease
M n SOD
glutathione
L H O N
ROS
+
-
Compensation
(patient and
tissue specific)
mtDNAc protein
mtTarea
ROS
mtTarea
+
-= MAI
mitochondrion
+
MPTP
Cyt C
Apoptosis
1a
1b
1c
2a
2b
determines patient
penetrance andtissue specificity
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WHERE IS THE BEST PLACE TOWHERE IS THE BEST PLACE TO
BLOCK APOPTOSIS?BLOCK APOPTOSIS?
1) 01) 0--1 hr: blocking TNF or FAS receptors1 hr: blocking TNF or FAS receptors
2) 12) 1--3 hrs: blocking mitochondrial pores3 hrs: blocking mitochondrial pores
3) 33) 3--6 hrs: blocking secondary6 hrs: blocking secondary capsasescapsases
4) 64) 6--8 hrs: DNA fragmentation8 hrs: DNA fragmentation
But processes not serialBut processes not serial