Formation of neuronal synapses by GDNF-induced cell adhesion

LEDDA, F

Herta Grande, Córdoba

Congreso; I Reunión Conjunta de Neurociencias I RCN; 2009

Sociedad Argentina de Investigación en Neurociencias y Taller Argentino de Neurociencias

The formation of neuronal synapses involves the precise assembly of the machinery responsible for neurotransmitter release at the presynaptic side and recruitment of neurotransmitter receptors to the postsynaptic density (PSD). Recent evidence indicates that cell adhesion molecules (CAMs) participate prominently in the key steps of synapse formation, inducing trans-synaptic adhesion and promoting an accurate alignment of pre- and postsynaptic terminals. The glial cell line-derived neurotrophic factor (GDNF) receptor GFRα1 is enriched at pre- and postsynaptic terminals in hippocampal neurons, suggesting that it has a role in synapse formation. We demonstrate that GDNF triggered trans-homophilic binding between GFRα1 molecules and cell adhesion between GFRα1-expressing cells. This represents the first example of a cell-cell interaction being mediated by ligand-induced cell adhesion molecule (LICAM). In the presence of GDNF, ectopic GFRα1 induced localize presynaptic differentiation in hippocampal neurons, as visualized by clustering of vesicular proteins and neurotransmitter transporters, and by activity-dependent vesicle recycling. Presynaptic differentiation was markedly reduced in neurons lacking GFRα1. Gdnf mutant mice showed reduced synaptic localization of presynaptic proteins and a significant decrease in the density of presynaptic puncta, indicating a role for GDNF signaling in hippocampal synaptogenesis in vivo. We propose that GFRα1 functions as a LICAM to establish precise synaptic contacts and induce presynaptic differentiation