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MANY Student questions of the dayMANY Student questions of the day……..Q1: Why do neurons have axons: wouldn’t
synapses between lots of small cells be just as good?
A1: Chemical synapses are slow, and transmission speedA1: Chemical synapses are slow, and transmission speed
down a neuron would plummet (by orders of magnitude).down a neuron would plummet (by orders of magnitude).
Q2: Why not have electrical synapses?
A2: These are rapid, but as any electrical synapse A2: These are rapid, but as any electrical synapse
would generate an action potential in the postsynaptic neuron, would generate an action potential in the postsynaptic neuron,
different inputs cannot be integrated.different inputs cannot be integrated.
Q3: Can one neuron get both excitatory and inhibitory inputs?
A3: Yes, these generally come from separate synapsesA3: Yes, these generally come from separate synapses
onto the same neuron. The neuron then summates these inputs onto the same neuron. The neuron then summates these inputs
to decide whether to generate an action potential.to decide whether to generate an action potential.
Q4: Are amphetamines neurotransmitters?
A4: No. Amphetamines alter neurotransmitter release/re-uptake.A4: No. Amphetamines alter neurotransmitter release/re-uptake.
7.013
4.23.07
Systems I
Nervous System 3
STARTSTARTFOUNDATIONSFOUNDATIONS
How-to 1How-to 1 FO
RM
AT
ION
FO
RM
AT
ION
How-to 2How-to 2
SYSTEMSSYSTEMS
PR
OB
LE
MS
PR
OB
LE
MS
BIOCHEM GENETICS CELL BIO.MOL. BIO
STEM
CELLS,
CLONING
REC. DNA
CELL TYPE &
POSITION
3DSTRUCTURE
GENOMICS
VIRUSES
CANCER
HUMAN
DISEASE
LIFELIFE
NERVOUS
SYSTEMIMMUNE
SYSTEMS
BIOLOGY
FUTUREFUTURE
excitatory/inhibitory
synapses
excitatory/inhibitory
synapses
sensory neuron interneuron motor neuron
input
output
CIRCUITaction potential
yes or no? action potential
yes or no?
action potential
yes or no?
H. Sive MIT 2007
Action potentials = message
Synapses = connections which regulate decision to “fire”
Circuits = which neurons connect
Input = neuronal, environmental: Output = movement, other
Circuits, synapses and action potentials1
Circuits
Zebra finch song circuit
2
Viewing words Listening to words
Speaking words Generating words
Purves 46.16: multiple brain nuclei (regions)
work together = language (PET scan)
3
Do neurons know where to go?
Do neurons know where to (re-)connect?
eye rotated 180o
NasalTemporal
4 Sperry’s frog retina rotation experiment
Experiment: rotate retina 180o, assay where axons regrow
5
H. Sive MIT 2007
retina optic tectum (brain)
T N R Cnormal
axon trajectories
R CN T
possible outcome:
axons find
incorrect targets
Conclusion: axons “know” where to grow
actual outcome:
axons find their
normal targetsR C
180o
rotated
retina
N T
Molecules involved in retinal axon migration
Nasal retinal axons choose to migrate on
rostral and not caudal tectal membranes
(stripe assay)
rostral
rostral
rostral
rostral
caudal
caudal
caudal
Tectal membrane6
retina optic tectum
N T R Cnormal
axon trajectories
Explaining Sperry’s retina rotation experiment
actual outcome:
axons find their
normal targets
T N
180o
rotated
retina
low
ephrin
ligand
high
ephrin
ligand
low eph receptor
high eph
receptor
R C
low
ephrin
ligand
high
ephrin
ligand
low eph receptor
high eph
receptor
Conclusion: N/T axons express different Eph receptor levels
and follow an ephrin gradient
Not covered
in lecture.
For your interest
only!!!
The growth cone
7
From Molecular Cell Biology/ Lodish
Zone of actin polymerization
Front/
leading edge
Direction of
movement
nucleus
Rear/
trailing
edgeLamellipodia/filopodia
Actin polymerization during cell movement
Remember this?! (Formation III)
axon
microtubules
microfilaments
(F-actin)
Filopodium/ lamellipodium
(thin) (thicker)
GROWTH
CONE
= Receptor
for short range/
long range guidance molecule
H. Sive MIT 2007
8
Axon guidance
via long/short range attractive/repulsive signals
Ballabore et al, 2005
9
growth cone
Axonal growth cone
10
Collapse of the axonal growth cone due to a repulsive signal
11
Guidance signals
Axonal outgrowth:
choice of laminin
versus
polylysine
substrate
12
Axon guidance in the
spinal cord: transverse section
floor plate
roof plate
trochlear
axons
grow
away from
floor plate
dorsal
ventral
commissural
axons grow
towards
and turn
at floor plate
Cell body
Growth cone
H. Sive MIT 2007
13
Spinal cord section
Commissural axons (green) , cell bodies (red)
Cell bodiesCell bodiescell bodies
axons
14
z
dorsal
spinal cord
floor
platecommissural
axon outgrowth
roof
plate
dorsal
spinal cordno outgrowth
Explant assay to test floor plate/roof plate activity
on commissural axonsH. Sive MIT 2006
15
Conclusion: floor plate attracts commissural axons
Explant assay for axon guidance activity
Dorsal spinal cord
Floor plate
Dorsal spinal cord
Tissue culture cells
growing
axons
no axon
outgrowth
16
Netrin1 RNA is
expressed
in floor plate
Netrin1 protein is
expressed in a gradient
extending from floor plate
Tessier-Lavigne et al
17
Wild type Netrin1-/-
Loss of function: Netrin is required for
normal commissural neuron (red) outgrowth
18
Netrin receptors promote attraction or repulsion
DCC-
DCC
netrin
attractive
Tyrosine kinases
GTPases (Rho)
Phosphoinositol
Cytoskeletal remodeling
(F-actin, microtubules)
Ca2+
influx
CAM Kinase
Growth cone extension/turning
Tyrosine kinases
Growth cone collapse
Cytoskeletal remodeling
G-actin
DCC-
UNC5
DCC-
UNC5
repulsive
netrin
H. Sive MIT 2007
plasma
membrane
19
Stabilizing connections
Nerve growth factor is a neuronal survival signal
(Prof. Rita Levi-Montalcini)
- NGF
+ NGF
20