Molecular mechanism of the synapse formation by neuronal activity

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How does neural activity remodel synapses? We previously reported a novel protocadherin designated Arcadlin was strongly induced in the brain by neural activity. Here, we show that this protocadherin Arcadlin is involved in the remodeling of spine membrane by regulating N-cadherin that that play a crucial role in synapse formation. Arcadlin synthesis is induced by neural stimulation and it is transported to the synaptic membrane, where it binds to N-cadherin. Overexpressed Arcadlin protocadherin drives N-cadherin into endosomes and suppresses the generation of dendritic filopodia and spines. Consistently, neurons from Arcadlin/PAPC homozygous mutant mice form a larger number of synaptic puncta than wild-type neurons. During our investigations into the intracellular signaling mechanism that activates the endocytosis of N-cadherin with Arcadlin, we identified a novel splice form of TAO2 kinase (TAO2β) as an intracellular binding partner of the Arcadlin protocadherin. Homophilic interacti … More on of Arcadlin on cell surface activates p38 MAPK through the activation of TAO2β. In turn, active p38 MAPK feeds back on TAO2β, phosphorylating its carboxy-terminal domain at a specific Serine. This triggers the co-endocytosis of N-cadherin/Arcadlin/TAO2β complex in HEK293T cells and hippocampal neurons. We propose that endocytosis regulated by this novel signal transduction pathway involving a protocadherin, a MAPKKK that binds to its intracellular domain, a MAPK and a classical cadherin modulates the adhesiveness and morphology of spine membranes, resulting in changes in synaptic strength induced by neural activity. In the future, it will be interesting to investigate behavior and memory in mice mutant for the Arcadlin protocadherin. The adhesive apparatus of synaptic spine membranes in the peri-synaptic region can now be recognized as a focal point of vigorous remodeling. Involvement of p38 MAPK-induced endocytosis may provide a possible relationship between the modulation of adhesive machinery and the insertion/removal of neurotransmitter receptors. Less