neuron lecture 2012 de camilli final amedcell.med.yale.edu/lectures/files/neurons.pdf · neuron...
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Neurons(and glial cells)
Pietro De Camilli
October 11, 2012
Human Brain
Golgi Stain
Camillo Golgi
Cajal
Genetically encoded dyes
green fluorescent proteinAequorea victoria
Jeff Lichtman
Martin Chalfie
Roger Tsien
Jeff Lichtman
Brainbows
Genetically encoded dyes
Neurons have a variety of shapes
axon
dendrites
Neuron as polarized cells
axon
Stages of axonal development (in vitro)
Dotti and Banker
(typically only one)
Red: axonal markerGreen: dendritic marker
Nerve cell grown in vitro
DENDRITES(INPUT)
AXON(OUTPUT)
Axon and dendrites have different properties
perikaryonsomacell body
http://www.clp.northwestern.edu/news/rewrite-textbooks-findings-challenge-conventional-wisdom-how-neurons-operate
Inhibitory interneuron (dendrites blue, axon red) shown adjacent to a schematic
of a hippocampal pyramidal neuron
Both dendrites and axons can be extremely branchedaxons are typically longer (can be much longer)
axon and dendrites of a single neuron
Demian Barbas, Luc DesGroseillers, Vincent F. Castellucci, et al. Learn. Mem. 10: 373, 2003
Neurons are organized in neuronal circuits
Schematic diagram of the neuronal circuit mediating tail and siphon withdrawal reflex in Aplysia (an invertebrate organism)
Key compartments of the neuron:
cell body (soma, perikaryon)dendritesaxons
Motor NeuronsVentral Horn
Dendrite
Nissl substance = RERCell body or perikaryon
Axon hillock
blood capillary
Neuronal perikarya
Most organelles of the cell body extend into the main dendritic branches
Motor NeuronsVentral Horn
Dendrite
Nissl substance = RERCell body or perikaryon
Axon hillock
blood capillary
Neuronal perikarya
Axon hillock
Entry of organlles in axons is selective. There are no rough
endoplasmic reticulum or ribosomes (and thus no protein synthesis) and Golgi complex in
mature axons
axons
Dendritic trees
Purkinje cells (cerebellum)
Purkinje cells (cerebellum)
Purkinje cells (cerebellum)
Purkinje cells (cerebellum)
Dendritic spines
Neuron Cytoplasm
Golgi Complex
RER
Golgi complex
Neuron Cytoplasm
Golgi Complex
RER
immunofluorescence
Silver impregnation(From Camillo Golgi)
Golgi complex
Axon sizeThe length of the axons
poses special needs:
-Structural support-Assisted organelle transport-Local synthesis and degradation of metabolites-Signal propagation
Unmyelinated Axons
Axons are surrounded by glial cells
AxonMyelinated
axon
Schwann cells (PNS)Oligodendrocytes (CNS)
Axons are surrounded by glial cells
Myelin
Development of myelin Node of Ranvier
Myelin
Development of myelin Node of Ranvier
Node of Ranvier, EM
Node of Ranvier
Nodes of Ranvier
βIV-spectrinK+ channelK+ channel Na+ channel
mutation:quivering mouse
Myelinated Axonlongitudinal-section
Quick-freeze-deep-etch viewFrom Hirokawa
A prominent cytoskeletal scaffold
Axonal transport• Anterograde, slow 2-4 mm/day
– cytosolic proteins, cytoskeletal elements…• Anterograde, fast (kinesins) 100-400 mm/day
– organelles, particles
• Retrograde, fast (cytoplasmic dynein)– organelles, particles (retrograde signaling, targeting to
lyososomes)
Organelle transport(microtubular motors in axonal cytoplasm)
From Paul ForscherFrom Nabutaka Hirokawa
Microtubular motors:kinesin(s) and cytoplasmic dynein
A multiplicity of kinesins(different cargo vesicles)
Weiss axoplasmic flow
Proximal to axonal block Distal to axonal block
From Tsukita and Ishikawa
Axonal block
From Broadwell and Cataldo, 1984
A continuous smooth ER from the cell body to axon terminal
arrows = endoplasmic reticulum
Several forms of hereditary spastic paraplegias are due to mutations in proteins that control the shape and the dynamics of the ER
closedinactivated
openedclosed
unmyelinated nerveConduction 0.6-2 m/sec + + + +
+ + + + ++ + + + +
- - - - - + +
Signal propagation in axons
Na+
Na+K+
K+
140 mM
17 mM
4.6 mM
90 mM
-70 mV
Unmyelinated nerve
gradient of Na+ and K+ across the plasma membrane is mantained by Na+/K+ ATPase
Na+ channel
inactivated opened closed
Conduction 5-120 m/sec - -
- -
+ +
+ +
Signal propagation in axonsMyelinated nerve
Saltatory conduction
nodes of Ranvier
DIC
Microtubules
ActinfilamentsLab of Paul Forscher Elke Stein
Growth cones
attraction/repulsion
Growth Cone
Lab of Paul Forscher, Yale
Axonal Degeneration and Regeneration
Axon regeneration occurs in the peripheral
nervous system but does not occur in the white matter of the
central nervous system
white matter gray matter
Model organisms
302 neurons (instead of billions as in the human brain)
Caenorhabditis elegans
daf-18 mutantwild type
Colon Ramos labAIY neurons
tools to study principles in neurons and circuits development
Axonal Regeneration
RegenerationAxotomy
Lab of Marc Hammarlund, Yale CNNR
Glial cells
Glial cells
Glial cells
ASTROCYTES
Structural supportPhysical isolation of neuronsBuffer of extracellular ions (f.e.sink for K+)Uptake /clearance of of neurotransmittersMetabolic functions to support neuronsSecretion of growth factorsResponse to injuryBlood-brain barrier
Astrocyte
Radial gliatracks for neuronal migration during brain development
developing cerebral cortex: the youngest cells are the ones closests to the pial surface
from F. Polleaux
Myelin generating cells:Oligodendrocytes (CNS) & Schwann cells (PNS)
Schwann cells = peripheral nervous system
Oligodendrocytes = central nervous system
Multiple Sclerosis (MS)
1. Inflammation2. Demyelination3. Impairment of nerve conduction4. Neurological deficits
Macrophage engulfing myelin in experimental autoimmune
encephalytis (EAE)����mouse model for MS
plaques
RemyelinationI. Recruitment phase
(Proliferation, Migration)
Acute lesion Recruitment of OPCs
Oligodendrocyte progenitor cells (OPCs)Franklin NatRevNeurosci 2002
Microgliathe macrophages of the brain
Microglia
Wenbiao Gan (NYU)
Neurodegeneration
Alzheimer plaques
iPS cells
Dimos/Eggan Lab at HSCI.
Motor neurons from patient with ALS
John B. Gurdon, Shinya Yamanaka2012 Physiology and Medicine Nobel Prize
Gensat projecthttp://www.gensat.org/index.html
NIH funded, publicly available gene expression atlas of the developing and adult nervous system
different shapes and differential gene expression