Synapse formation
Raghav Rajan
Bio 334 – Neurobiology I
September 5th 2013
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
1
Synapses are the connections between two neurons –
can be electrical or chemical
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5th September 2013
Typical chemical
synapse
Presynaptic axon
Postsynaptic
dendrite
Synaptic cleft
Since they are small
– difficult to
visualize
Considerable
debate about their
presence
Bio 334 - Neurobiology I - Synapse and map formation
http://en.wikipedia.org/wiki/File:Active_zone3.JPG
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Synapses evolved about 1.1 million years ago, but
some components were present even earlier
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
http://www.lscp.net/persons/ramus/fr/GDP1/papers/verhage00.pdf
3
Complexity of the signalling process in the
postsynaptic density has increased greatly
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
http://www.lscp.net/persons/ramus/fr/GDP1/papers/verhage00.pdf
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Synapse location and number are not random – instead
they are regulated
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Excitatory synapses
are typically on
spine heads
Inhibitory synapses
are typically on
cell bodies,
proximal dendrites
or spike necks
Synapse number
can vary depending
on target neurons
http://www.richardsmrt.com/?page_id=86
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
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Three general observations related to synapse
formation
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Synaptic building blocks are manufactured by neurons
even before they make contacts with each other
Intercellular signaling, signals from glia, extracellular
matrix, neighbouring neurons – all participate in
synaptogenesis
Synapses mature over the course of development –
experience dependent plasticity, critical periods, etc....
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
6
Study of synapses gained speed in 1950s with the
advent of two new techniques
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Electron microscopy
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Intracellular recordings
http://faculty.washington.edu/chudler/java/em.html
http://en.wikipedia.org/wiki/File:RL_Squid_Synapse_2.jpg
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
7
Pre and post-synaptic membranes come close to each
other in a newly formed synapse
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But, not much can
be seen in terms
of presynaptic or
postsynaptic
specializations
Difficult to see
newly forming
synapses – since
there is nothing
much to see at
this stage
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
8
A lot of information about synapse formation comes
from watching synapse formation in culture
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5th September 2013
After contact,
filopodia retract
Slowly pre and
post-synaptic
parts mature
Extracellular
matrix also
matures
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
9
Important features of synapses - location, location,
location – but how is this determined
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Inputs far away on
the dendritic tree
have less impact at
the cell body
Recent studies
show that this is
not entirely true –
may depend on the
properties of
dendrites in
different neurons
http://www.sciencedirect.com/science/article/pii/S0960982200000348?np=y
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
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First synapses form on growth cones or extremities –
later on cell bodies
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Axo-dendritic synapses onto dendritic growth cones
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Axo-muscle synapses onto muscle myopodia
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May even be regulated by glia controlling accessibility to
various parts of the post-synaptic cell
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
11
Pre and post-synaptic structures can form independent
of partners
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Clustering of post-synaptic alpha-2 adrenergic receptors
without any presynaptic membrane in rat visual cortex
(p4)
Presynaptic terminal with vesicles in a Drosophila mutant
that does not make muscle
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
12
Synapse number increases after birth
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5th September 2013
Cat visual cortex
Neuron density decreases
with increased gliogenesis
But neuronal processes
grow and start making
synapses
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
13
Growth cones of axons can release neurotransmitters
spontaneously before formation of contacts
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
14
Functional synapses can form very quickly in culture
soon after contact
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5th September 2013
Muscle cell brought into
contact with neurite
Spontaneous currents and
evoked currents change
rapidly
Working synapse is produced
quickly
But, functional maturation
can take days to weeks
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
15
Stages in synapse formation – 1 – contact formation –
Ca2+, PKC, cAMP all play a role
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5th September 2013
Contact with the correct
postsynaptic target can induce
a Ca2+ increase in the growth
cone triggering cytoskeletal
changes
Astrocytes also play a role in
this process
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
16
Stages in synapse formation – 2 – Increase in adhesion
between growth cone and target cell
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5th September 2013
Increase in adhesion between
growth cone and target cell
within 15 minutes of contact
Nectins, cadherins, etc....
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
17
Stages in synapse formation – 3 – converting sticky
growth cone to a presynaptic terminal
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Presynaptic terminals can
mature quickly without
concomitant maturation of
postsynaptic partners
Mature forms of either partner
can stimulate maturation of the
other
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous
System 2005 – Chapter 8
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
18
Signaling pathways again ..... they can change growth
cones into presynaptic terminals
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5th September 2013
Different
signaling
pathways
activated by
contact
stimulate
change of
growth cone
into
presynaptic
terminal
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
19
Postsynaptic clustering of receptors can be
autonomous
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5th September 2013
ACh receptors stained
with alpha-bungarotoxin
Mouse diaphragm muscle
Localization in the centre
even in mutants without
axon ingrowth
Stabilization by
presynaptic contact
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
20
Postsynaptic clustering of receptors can also be
induced by contact with the right neurons
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5th September 2013
Clustering can be induced by
contact
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
21
Agrin, a proteoglycan, is another cluster-inducing
molecule
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5th September 2013
In this case, basal lamina also
produce agrin and can induce
clustering of post-synaptic Ach
receptors (frog NMJ)
Agrin also produced by motor
neurons
Bio 334 - Neurobiology I - Synapse and map formation
Dan H Sanes, Thomas A Reh, William A Harris. Development of the Nervous System 2005 – Chapter 8
22
Overall take home of synapse formation
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Highly specific in terms of location and connections
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Both sides play a role
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And there may be other players – glia, extracellular
matrix
The order of events is not completely understood – may
be different for different synapses
NOT FIXED – STILL ROOM FOR PLASTICITY
5th September 2013
Bio 334 - Neurobiology I - Synapse and map formation
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