Cours : Synapse formation (II) and Synapse plasticity

Synapse Formation and Plasticity

• Synapses are fundamental for communication between neurons
• Synapse formation is a complex process involving several stages
• Synapse development involves both pre and postsynaptic components
• Synaptic evolution likely occurred more than once in different lineages.
• Many organisms do not even need synapses.
• Synaptic strength is determined by multiple factors, including neurotransmitter release probability.

Synaptic Modules

• Synapses are composed of three main components: vesicle fusion, active zone, and postsynaptic density.
• Vesicle fusion can occur in the absence of cytoplasmic scaffolds or Ca2+.
• Functional presynapses can form without a postsynaptic partner

Active Zone Assembly

• Presynaptic lysosome-related vesicles (PLVs) contain active zone proteins and synaptic vesicle proteins.
• Partial axonal co-transport in PLVs transport these components in Drosophila and human neurons.

Genes Involved in Active Zone Assembly

• Genes such as dsyd-1 (Drosophila) and msyd-IA (mouse) are crucial for synaptic vesicle targeting in both the peripheral nervous system (PNS) and central nervous system (CNS).

Evolutionary Conservation

• Molecular mechanisms underlying synapse development are conserved between flies and mice (~700 million years apart)

Today's Synaptic Assemblies

• Todays synapse assemblies include postsynaptic assembly, postsynaptic & transsynaptic molecules, maturation, and plasticity.

Postsynaptic Density

• Neurexin expression in non-neuronal cells influences glutamate and GABA postsynaptic protein clustering in dendrites.
• Neuroligin isoforms determine the polarity of synapses(inhibitory or excitatory).

Postsynaptic Density Assembly

• Neuroligin expression in non-neuronal cells may induce the accumulation of postsynaptic scaffolding proteins in dendrites.
• Neurexins mediate excitatory postsynaptic formation and Neuroligins mediate inhibitory postsynaptic formation

Synaptic CAMs

• Specific cell adhesion molecules (CAMs) are expressed in non-neuronal cells, that induce pre/postsynaptic features when in co-culture with neurons.
• Specific CAMs, e.g. Neuroligins, regulate the formation of presynaptic and postsynaptic compartments.

PSD Assembly

• 'Non-synaptic'   postsynaptic protein clusters and 'Synaptic' postsynaptic proteins differ in their behavior in formation.
• Some postsynaptic scaffolding proteins transport in a coordinated or non-coordinated manner that dictates whether a synapse will form.
• Some postsynaptic proteins (like PSD-95) accumulate at active synapses after a period of neuronal activity after uncaging glutamate.

Activity-Dependent Processes

• Synaptic activity can trigger glutamate uncaging which results in the grow of a post synaptic structures such as spines.
• Neuroligin 1 facilitates glutamate uncaging-induced spinogenesis.
• The presynaptic protein Munc13 may represent presynaptic release sites.
• Normal spine development and glutamate uncaging occur in Munc-1/3 double knock-out mice.

PALM of PSD-95

• Photoactivated localization microscopy (PALM) can be used to quantify the number of PSD-95 molecules.

Pre/Post Alignment

• PALM shows alignment of presynaptic and postsynaptic proteins into “nanocolumns”.

Timing of Synaptogenesis

• Cell adhesion molecules (CAMs) orchestrate the timing between pre and post synapic assembly, in general, presynaptic assembly comes before the postsynaptic assembly, in certain cases this may not hold true.

Synapse Maturation

• Synapse maturation involves the refinement of synaptic topography, convergence, and postsynaptic compartment.
• Numerous synapses are typically pruned during the maturation process of development. The elimination of synapses follows a pattern, involving both segregation and specific activity-levels of the neurons involved.
• In vivo mouse NMJs (neuromuscular junctions) serve as a model for investigating synaptic maturation.
• Synapse elimination is accompanied by input segregation and eventually terminal withdrawal.
• Patterns of motor neuron activity influence synapse elimination during neural development.
• The “winner synapse” undergoes LTP, resulting in its strengthening and leading to the elimination of the remaining synapses.

Synaptic Plasticity and Competition

• Synchronous activation of climbing fibers and Purkinje cells (PCs) can lead to long-term potentiation (LTP).
• LTP at large inputs results in enhanced AMPA-type glutamate receptor conductance.

How to Build a Synapse

• Synaptogenesis occurs through transitive signaling primarily mediated by cellular adhesion proteins.
• Synaptic activity plays a role in both the activation and deactivation of synapse processes.

Summary of Findings

• The formation of synapses is a complex process regulated by various factors including molecular mechanisms, and neural activity.
• Synaptic plasticity and competition play critical roles in synapse formation, maturation, and structure.