PI3K couples long-term synaptic potentiation with cofilin recruitment and actin polymerization in dendritic spines via its regulatory subunit p85α

• Published in: Cellular and molecular life sciences : CMLS 2024-08, Vol.81 (1), p.358
• Main Authors: López-García, Sergio, López-Merino, Esperanza, Fernández-Rodrigo, Alba, Zamorano-González, Pablo, Gutiérrez-Eisman, Silvia, Jiménez-Sánchez, Raquel, Esteban, José A.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Actin; Actin Depolymerizing Factors - metabolism; Actins - metabolism; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Catalytic activity; Catalytic converters; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell Biology; Cells, Cultured; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Cofilin; Coupling (molecular); Cytoskeleton; Dendritic plasticity; Dendritic spines; Dendritic Spines - metabolism; Dendritic structure; Dynamic structural analysis; Functional plasticity; Glutamic acid receptors (ionotropic); Glutamic acid receptors (metabotropic); Hippocampal plasticity; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Imaging techniques; Kinases; Life Sciences; Long-term depression; Long-term potentiation; Long-Term Potentiation - physiology; Mice; Molecular modelling; N-Methyl-D-aspartic acid receptors; Neuronal Plasticity - physiology; Neurons - metabolism; Original; Original Article; Phosphatidylinositol 3-Kinases - metabolism; Plasticity; Polymerization; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Rats; Regulatory mechanisms (biology); Regulatory subunits; Signal Transduction; Structure-function relationships; Synapses; Synapses - metabolism; Synaptic depression; Synaptic plasticity; Synaptic strength; Synaptogenesis
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-024-05394-x

Long-term synaptic plasticity is typically associated with morphological changes in synaptic connections. However, the molecular mechanisms coupling functional and structural aspects of synaptic plasticity are still poorly defined. The catalytic activity of type I phosphoinositide-3-kinase (PI3K) is required for specific forms of synaptic plasticity, such as NMDA receptor-dependent long-term potentiation (LTP) and mGluR-dependent long-term depression (LTD). On the other hand, PI3K signaling has been linked to neuronal growth and synapse formation. Consequently, PI3Ks are promising candidates to coordinate changes in synaptic strength with structural remodeling of synapses. To investigate this issue, we targeted individual regulatory subunits of type I PI3Ks in hippocampal neurons and employed a combination of electrophysiological, biochemical and imaging techniques to assess their role in synaptic plasticity. We found that a particular regulatory isoform, p85α, is selectively required for LTP. This specificity is based on its BH domain, which engages the small GTPases Rac1 and Cdc42, critical regulators of the actin cytoskeleton. Moreover, cofilin, a key regulator of actin dynamics that accumulates in dendritic spines after LTP induction, failed to do so in the absence of p85α or when its BH domain was overexpressed as a dominant negative construct. Finally, in agreement with this convergence on actin regulatory mechanisms, the presence of p85α in the PI3K complex determined the extent of actin polymerization in dendritic spines during LTP. Therefore, this study reveals a molecular mechanism linking structural and functional synaptic plasticity through the coordinate action of PI3K catalytic activity and a specific isoform of the regulatory subunits.