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Neurobiol Dis ; 198: 106558, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852754

RESUMO

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flnaflox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations.


Assuntos
Córtex Cerebral , Filaminas , Proteínas rac1 de Ligação ao GTP , Animais , Camundongos , Fatores de Despolimerização de Actina/metabolismo , Córtex Cerebral/metabolismo , Filaminas/metabolismo , Filaminas/genética , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Camundongos Transgênicos , Neurogênese/fisiologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Neuropeptídeos/genética , Heterotopia Nodular Periventricular/genética , Heterotopia Nodular Periventricular/metabolismo , Heterotopia Nodular Periventricular/patologia , Células Piramidais/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética
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