Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus

• Published in: Current biology 2016-10, Vol.26 (19), p.2551-2561
• Main Authors: Marzo, Aude, Galli, Soledad, Lopes, Douglas, McLeod, Faye, Podpolny, Marina, Segovia-Roldan, Margarita, Ciani, Lorenza, Purro, Silvia, Cacucci, Francesca, Gibb, Alasdair, Salinas, Patricia C.
• Format: Article
• Language: English
• Subjects: Animals; Female; Hippocampus - physiopathology; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Male; Memory, Long-Term; Mice; Mice, Transgenic; Neuronal Plasticity; Synapses - physiology; Wnt Signaling Pathway
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2016.07.024

Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer’s disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration. [Display omitted] •Wnt signaling is required for synapse integrity in the adult hippocampus•Dkk1 induces synapse loss and deficits in synaptic plasticity and long-term memory•Dkk1 disassembles synapses by activating the Gsk3 and Rock pathways•Synapse loss and memory defects are reversible by reactivation of the Wnt pathway Deficiency in Wnt signaling has been implicated in Alzheimer’s disease. Marzo et al. elucidate the impact of the Wnt antagonist Dkk1 in the adult hippocampus, showing synapse loss and defects in synaptic plasticity and long-term memory. They also reveal that cessation of Dkk1 expression induces synapse regeneration and recovery of long-term memory.