Activity-dependent homeostasis of membrane excitability.

MURARO NI; BROOKE H; BAINES RA

Barcelona

Congreso; 8th FENS Forum of Neuroscience; 2012

HE FEDERATION OF EUROPEAN NEUROSCIENCE SOCIETIES (FENS)

Central neurons adapt to changing patterns of synaptic excitation. These adaptations are essential to prevent neurons from either falling silent as synaptic excitation falls, 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 saturation or quiescence. 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 shown 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 show 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.