synapse formation

5th September 2013 Bio 334 - Neurobiology I - Synapse and map formation 1

Synapse formation

Raghav RajanBio 334 – Neurobiology I

September 5th 2013


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


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


Complexity of the signalling process in the postsynaptic density has increased greatly

http://www.lscp.net/persons/ramus/fr/GDP1/papers/verhage00.pdf


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


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....


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

http://faculty.washington.edu/chudler/java/em.html


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


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



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


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


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



Synapse number increases after birth

● Cat visual cortex● Neuron density

decreases with increased gliogenesis

● But neuronal processes grow and start making synapses



Growth cones of axons can release neurotransmitters spontaneously before

formation of contacts



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



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



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....



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



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



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



Postsynaptic clustering of receptors can also be induced by contact with the right neurons

● Clustering can be induced by contact



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



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

synapse formation

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