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5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 1
Synapse formation
Raghav RajanBio 334 – Neurobiology I
September 5th 2013
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 2
Synapses are the connections between two neurons – can be electrical or chemical
● Typical chemical synapse
● Presynaptic axon● Postsynaptic
dendrite● Synaptic cleft● Since they are small
– difficult to visualize
● Considerable debate about their presence
● Synapse – term coined by Charles Sherringtonhttp://en.wikipedia.org/wiki/File:Active_zone3.JPG
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 3
Synapses evolved about 1.1 million years ago, but some components were present even earlier
http://www.lscp.net/persons/ramus/fr/GDP1/papers/verhage00.pdf
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 4
Complexity of the signalling process in the postsynaptic density has increased greatly
http://www.lscp.net/persons/ramus/fr/GDP1/papers/verhage00.pdf
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 5
Synapse location and number are not random – instead they are regulated
● 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 6
Three general observations related to synapse formation
● 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 7
Study of synapses gained speed in 1950s with the advent of two new techniques
● Electron microscopy● Intracellular recordings
http://faculty.washington.edu/chudler/java/em.htmlhttp://en.wikipedia.org/wiki/File:RL_Squid_Synapse_2.jpg
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 8
Pre and post-synaptic membranes come close to each other in a newly formed synapse
● 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
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 9
A lot of information about synapse formation comes from watching synapse formation in
culture● After contact,
filopodia retract● Slowly pre and
post-synaptic parts mature
● Extracellular matrix also matures
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 10
Important features of synapses - location, location, location – but how is this determined
● 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 neuronshttp://www.sciencedirect.com/science/article/pii/S0960982200000348?
np=y
5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 11
First synapses form on growth cones or extremities – later on cell bodies
● Axo-dendritic synapses onto dendritic growth cones● Axo-muscle synapses onto muscle myopodia
● 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 12
Pre and post-synaptic structures can form independent of partners
● 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
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 13
Synapse number increases after birth
● Cat visual cortex● Neuron density
decreases with increased gliogenesis
● But neuronal processes grow and start making synapses
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 14
Growth cones of axons can release neurotransmitters spontaneously before
formation of contacts
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 15
Functional synapses can form very quickly in culture soon after contact
● 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
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 16
Stages in synapse formation – 1 – contact formation – Ca2+, PKC, cAMP all play a role
● 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
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 17
Stages in synapse formation – 2 – Increase in adhesion between growth cone and target cell
● Increase in adhesion between growth cone and target cell within 15 minutes of contact
● Nectins, cadherins, etc....
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
Stages in synapse formation – 3 – converting sticky growth cone to a presynaptic terminal
● 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 19
Signaling pathways again ..... they can change growth cones into presynaptic terminals
● Different signaling pathways activated by contact stimulate change of growth cone into presynaptic terminal
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 20
Postsynaptic clustering of receptors can be autonomous
● ACh receptors stained with alpha-bungarotoxin
● Mouse diaphragm muscle
● Localization in the centre even in mutants without axon ingrowth
● Stabilization by presynaptic contact
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 21
Postsynaptic clustering of receptors can also be induced by contact with the right neurons
● Clustering can be induced by contact
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 22
Agrin, a proteoglycan, is another cluster-inducing molecule
● 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
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 23
Overall take home of synapse formation
● Highly specific in terms of location and connections● Both sides play a role● 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