Seeing the big picture. In some forms of epilepsy, ectopic nodules of neurons have been found below the cortex, close to the ventricles. But are ectopic neurons responsible for seizures? Here, the authors show that the FLNA mutation implicated in most periventricular nodular heterotopia leads to overgrowth of the dendritic arbor and alters spine maturation of properly placed cortical neurons. Thus, periventricular nodules may be a sign, not a cause, of global cortical network dysfunction at the origin of seizures.    (IB)

The authors: A Falace*, L Corbieres*, C Palminha, FC Guarnieri, F Schaller, E Buhler, C Tuccari di San Carlo, A Montheil, F Watrin, JB Manent, A Represa, A de Chevigny, E Pallesi-Pocachard & C Cardoso

Scientific abstract: 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.

Paru dans Neurobiology of Disease, 2024