IIBBA   05544
INSTITUTO DE INVESTIGACIONES BIOQUIMICAS DE BUENOS AIRES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Activity-dependent homeostasis of membrane excitability
Autor/es:
MURARO NI; BROOKE, H; BAINES, RA
Lugar:
Barceloma
Reunión:
Congreso; 8th FENS Forum of Neuroscience; 2012
Institución organizadora:
Federation of European Neuroscience Societies
Resumen:
Central neurons adapt to changing patterns of synaptic excitation. These adaptations are essential to prevent neurons from either falling silent as synaptic excitation drops, or from becoming saturated as excitation increases. In the absence of such circuit stabilizing mechanisms, activity-dependent plasticity that, for example, underpins embryonic neuronal development and memory and learning, including long-term potentiation and long-term depression, could drive neural activity to quiescence or saturation. Though these homeostatic mechanisms have been well documented, the underlying molecular mechanisms are poorly understood.  Our work exploits the molecular tractability of Drosophila to address these concerns. Drosophila motoneurons show increased action potential firing when deprived of excitatory synaptic drive and vice versa. We have shown that these changes in excitability are mediated by regulation of expression of the voltage-gated sodium current (INa), termed Dmnav (encoded by the paralytic gene). The changes to INa are mediated, at least in part, by activity-dependent translational repression of the Dmnav mRNA transcript. We will show that the translational repressor Pumilio is both necessary and sufficient for the activity-dependent changes observed in DmnavmRNA and INa. Sequence analysis of the Dmnav transcript shows it to contain a specific motif, termed a Nanos Response Elements (NRE), that has previously been proved necessary for Pumilio binding and repression of translation of other mRNA transcripts.  Mammalian neurons also show activity-dependent changes in membrane excitability and also express Pumilio. In a parallel study, we demonstrate that knockdown of rat Pumilio-2 is sufficient to increase both INa and action potential firing in cortical pyramidal neurons. Thus, it would seem that regulation of membrane excitability through translational control of sodium channel mRNA is a universal homeostatic mechanism.