FILAMIN A REGULATES DENDRITIC MORPHOLOGY AND HIPPOCAMPAL FUNCTION

Dendritic architecture, determining the specificity and capacity of synaptic input, is a critical determinant of neural computation. During neural development integrin-mediated cell in interaction with intracellular signaling and the cytoskeleton regulates where and when the dendritic arborization will take place. Filamin A (FlnA) is a key integrator of these processes and involved in integrin activation, actin filament crosslinking, detection of mechanical stress as well as modulation of intracellular signaling. We here describe that both increasing and decreasing FlnA expression in hippocampal neurons can significantly alter dendritic arborization in primary hippocampal neurons, albeit through different processes: while FlnA knockdown-induced hypertrophy is critically dependent on by integrin inside-out activation, overexpression of FlnA mediates similar effects in an integrin independent, but actin cytoskeleton dependent manner. Our data suggest a differential regulation of dendritic growth through FlnA level dependent regulation of integrin-actin interactions. FlnA thereby critically controls hippocampal information processing and behavior, as shown in vivo with CRISPR/Cas9-mediated knockout disrupting synaptic transmission in CA3 subregion of the mouse hippocampus and impairing pattern completion during fear conditioning. Together, our findings from both in vitro and in vivo approaches identify FlnA as a regulator of hippocampal morphology and circuit function, linking the control of dendritic branching to synaptic transmission and behavior.