Synaptogénèse

Synaptogenesis constitutes a major event in the brain. There is 10¹1 neurons making on average 7000 synapses.

They should be connected at the right time at the right place in the body but also at the level of the neuron.

Synaptopathies : autism, schizophrenia, mental retardation, etc.

A problem either with the connectivity, the size, or the synapse functioning.

A synapse is composed of a presynaptic and a postsynaptic elements.

Presynaptic : piccolo bassoon (structural element), synaptic vesicle (functional element)

The only difference between excitatory and inhibitory neuron is the nature of the neurotransmitter and the transporter.

Postsynaptic :

Scaffold molecule : specific to excitatory or inhibitory molecules

→ table of the most usual synaptic markers !

Part 1 : Central synapse formation

Stereotyped way to form synapses

A) Axonal competence → B) Adhesion and cohesion → C) recruitment of partners → D) Maturation or elimination

Guiding factors

Long-range cues : diffusion

Short-range cues : contact (adhesion molecules)

They can induce repulsive or attraction response.

Both long range and short range factors are integrated in the tissues in 3D. Axon guidance factors are secreted by intermediate targets or by the final target. Combinaison of guidance molecules to guide migratory cells , axons and refinement.

2) Priming factors

trans-synaptic formation : Signaling factors before neuronal contact, to give the axonal competence. This is neuronal factors secreted by the target neuron : FGF, TGFbeta, BDNF, Wnts, etc.

Induce a growth cone remodelling (a change the cytoskeleton), more synapses in the culture. Priming activity is neuron-specific. Tubulin is reorganized in a loop-like structure.

Wnt pathway : inhibit a kinase that do not induce phosphorylation of the MAP1B and allow the stabilisation of microtubules.

Development is depending on the dosage of molecules in space and time.

After the priming and the axonal competence achieved, we can also have an accumulation of vesicular proteins before pre and post contact. Cf FM dye in the notes about technics.

3) Functions of cell adhesion : molecules at synapses

They are involved in the recognition of partners, the size, position, the coordination of alignment, mechanica cohesion, pre and post compartments organization.

Simple cell adhesion molecules : implicated in the recognition of the adequate partner (cadherins, protocadherins, NCAM, neurofascin, from broadly to highly specifics). They are present on axonal and dendritic membranes before the contact.

Cadherins are transmembrane, that have five domains extracelular, one dimer of cadherin recognizes the same dimer of another cadherin between two different cells. If you have more than five domains the interaction will be very hard. Differents cadherins are expressed in different domains of the cerebellum, sometimes we can found combinaison of cadherins, this allow neurons to “know” where to connect their axons.

Cadherins are found only in excitatory neurons. The distribution of cadherins in synapses change between immature and mature synapses.

Fasciculation : when axons gather, expanding together.

Some cell adhesion molecules are broadly expressed, some show a very restricted expression.

For example, Neurofascin is involved in Basket cell / Purkinje cell synapses.

“Complex” cell adhesion molecules

Induce the formation of the synapse. There factors that start the recruiting process of other actors.

Major “complex” cell adhesion molecules (à insérer)

Neurexin / Neuroligin complex :

Transmembrane protein, with an intracellular and extracellular domains, having two places splicing sites, there are 4 variants.

How o find out if a transmembrane protein has an effect in synapse formation?

Experiment :

HEK cells (Human Embryonic Kidney cells, fibroblasts transfected with neuroligin-GFP, control with GFP alone, that will be expressed at the membrane) and neurons in culture: the axons of the neurons tend to go to the location where they can find neuroligin and

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