Multiple signaling pathways are essential for synapse formation induced by synaptic adhesion molecules

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Synapse formation is fundamental for neural circuit function.
• The specific cellular signals and pathways governing synapse organization remain largely unknown.

Purpose of the Study:

• To identify signaling pathways involved in synapse formation.
• To elucidate the roles of specific kinases in organizing pre- and postsynaptic specializations.

Main Methods:

• Utilized heterologous synapse formation assays with nonneuronal cells expressing synaptic adhesion molecules.
• Employed pharmacological inhibitors for kinases (JNK, PKA, AKT, MAP kinases, PKC) and cytoskeletal components (microtubules, actin).
• Investigated AKT signaling by targeting PTEN (phosphatase and tensin homolog) to postsynaptic sites.

Main Results:

• Interference with microtubules and actin filaments impaired synapse formation.
• Inhibition of c-jun N-terminal kinases (JNKs), protein kinase-A (PKA), and AKT kinases suppressed heterologous synapse formation.
• JNK and PKA inhibition affected both pre- and postsynaptic specializations, while AKT inhibition primarily impacted postsynaptic development.
• Targeting PTEN to postsynaptic sites impaired postsynaptic formation and reduced excitatory synapse function.

Conclusions:

• Heterologous synapse formation is orchestrated by a complex kinase network.
• Distinct signaling pathways, including JNK, PKA, and AKT, play specific roles in organizing presynaptic and postsynaptic specializations.
• These findings provide insights into the molecular mechanisms underlying synapse development.