Synapse recovery after synapse degeneration: a role for Wnt signalling
Our laboratory is studying the molecular mechanisms that modulate the formation, function and maintenance of synapses in the healthy and diseased mammalian brain. Our studies on Wnt signalling have led to the discovery that these secreted proteins promote the formation and stability of synapses in the hippocampus, an area implicated in learning and memory. Wnts also modulate synapse stability and function in the striatum, which control motor function. More recently, we reported that dysfunction of Wnt signalling contributes to the pathogenic activity of Amyloid-ß at central synapses. To examine the contribution of deficient Wnt signaling in synapse degeneration in the adult hippocampus, we have generated an inducible transgenic mouse model that expresses a secreted and specific Wnt antagonist Dickkopf-1 (Dkk1) upon exposure to doxycycline. We found that blockade of Wnt signalling leads to synapse loss, long-term plasticity defects and deficits in long-term memory. These defects are very similar to those observed in mouse models of Alzheimer’s disease. Taking advantage of our inducible transgenic model, we asked whether reactivation of Wnt signaling restores synaptic connectivity at the cellular and circuit level. I will be presented new results that reveal the remarkable capacity of the adult brain to reassemble functional neuronal circuits after substantial synapse degeneration. These findings highlight the therapeutic potential of the Wnt pathway in neurodegenerative diseases like AD.