Synapse Formation: Neuronal Development

• Lecture focuses on synapse formation, a critical process for establishing functional neural circuits, shifting from neuronal survival and death.

Defining a Neuron

• Neurons are defined by synapses, which are key features distinguishing them from other cell types.
• Neurons have dendrites, soma (cell body), and axon that enable directional information flow.
• Neurons utilize membrane potential and generate action potentials for long-distance signaling.
• Synapses are specialized junctions enabling neuron communication with each other and other cells like muscle cells.

Synapse Formation: A Two-Sided Story

• Requires coordinated effort between presynaptic and postsynaptic partners.

Presynaptic Differentiation

• Target Recognition: first involves the growth cone identifying the appropriate target cell and specific site for synapse formation.
• Synaptic Junction Formation: initiated by the growth cone forming a specialized junction with the target cell.
• Presynaptic Specialization: occurs when the growth cone matures into a presynaptic terminal, acquiring molecular machinery for neurotransmitter synthesis, storage, and release.

Postsynaptic Differentiation

• Afferent Recognition: requires the postsynaptic target cell to recognize and respond to the incoming growth cone.
• Synaptic Junction Formation: occurs as the postsynaptic cell participates in the assembly of the synaptic junction, aligning its cellular machinery with the presynaptic terminal.
• Postsynaptic Specialization: involves the postsynaptic site maturing to include neurotransmitter receptors, scaffolding proteins to anchor these receptors, and signaling molecules to transduce the neurotransmitter signal.
• Stable, functional synapse establishment needs bidirectional communication between pre- and postsynaptic partners.

Growth Cones: Equipped for Synaptic Communication

• Growth cones possess a basic neurotransmitter release system.
• Growth cones possess the molecular components for synaptic vesicle fusion and neurotransmitter release.

Sensing the Right Target

• Growth cones actively seek appropriate synaptic partners.
• Growth cones exhibit a surge in intracellular calcium ([Ca2+]i) upon encountering an appropriate target.
• Calcium influx is crucial for initiating presynaptic differentiation.
• Increase in growth cones can be mimicked by elevating cyclic AMP (cAMP) levels.
• Target recognition involves cAMP-dependent protein kinase (PKA).

Cell Adhesion: Bringing Partners Together

• Cell adhesion molecules physically link pre- and postsynaptic partners once the appropriate target is identified.
• Synapse formation involves NCAM, S-laminin, synCAM, cadherins, and nectins.
• These molecules stabilize the nascent synaptic junction and promote further differentiation of pre- and postsynaptic compartments through trans-synaptic interactions.

Rapid Enhancement of Transmission

• Efficiency of synaptic transmission rapidly strengthens upon initial contact.
• Enhancement due to the coordinated transport and assembly of presynaptic components.
• Presynaptic components are transported in discrete packets along the axon and these packets are stabilized at sites of synaptic contact, and this contributes to the rapid maturation of the presynaptic terminal.

Synapse-Inducing Factors: Orchestrating the Process

• Molecular cues act as potent synapse-inducing factors.
• The interaction between presynaptically localized neurexins and postsynaptically localized neuroligins is crucial for synapse formation in various brain regions, and disrupting this interaction impairs synapse development.
• The binding of presynaptic Frizzled receptors to postsynaptically secreted Wnt-7a promotes synapse formation, similarly to neurexin-neuroligin.
• Glial cells secrete factors like thrombospondin that facilitate synapse formation and convert silent synapses into functional synapses.

NMJ: A Model for Synapse Formation

• The neuromuscular junction (NMJ) is a specialized synapse between a motor neuron and a muscle fiber.
• NMJ serves as a model system for studying synaptogenesis due to its large and accessible synapse.
• NMJ uses a single neurotransmitter (acetylcholine), a single primary receptor type (AChR), a one-to-one innervation pattern, and is large compared to central synapses.