Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

Abstract

Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions. autocrine Wnt signaling | dendrite arbors | adult hippocampus

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

“…It was previously shown that Wnt ligands that signal through the canonical Wnt/β‐catenin pathway regulate proliferation and fate commitment of NPCs; however, the role of noncanonical Wnt ligands on adult neurogenesis has been less explored. Here, we investigated the role of Wnt5a, which is expressed in the adult hippocampus and in AHPs, and it is known to activate noncanonical Wnt/JNK and Wnt/Ca +2 signaling pathways in cultured hippocampal neurons, and Wnt/JNK signaling in differentiating AHPs . We determined that genetic knockdown of Wnt5a in the dentate gyrus decreased the generation of adult‐born neurons.…”

“…Previous studies have involved CaMKII in activity‐dependent dendrite development of cultured hippocampal neurons, and in Wnt7b‐induced dendritogenesis in cultured pyramidal neurons . In addition, CaMKII is involved in Wnt5a‐dependent maintenance of dendritic arborization in CA1 pyramidal neurons of the adult hippocampus . Therefore, it is likely that in the adult dentate gyrus, Wnt5a signals through the Wnt/CAMKII pathway to regulate morphogenesis of adult‐born neuron.…”

“…38 In the present study, we investigated the role of the noncanonical ligand Wnt5a, which is expressed in the adult hippocampus. Wnt5a mRNA is enriched in the dentate gyrus and the CA1 region of adult mice, 39 and the Wnt5a protein is highly expressed in the adult hippocampus. 39,40 In cultured hippocampal neurons, Wnt5a regulates developmental axon and dendrite outgrowth, 41,42 synapse formation, 43 and dendritic spine formation.…”

“…Wnt5a mRNA is enriched in the dentate gyrus and the CA1 region of adult mice, 39 and the Wnt5a protein is highly expressed in the adult hippocampus. 39,40 In cultured hippocampal neurons, Wnt5a regulates developmental axon and dendrite outgrowth, 41,42 synapse formation, 43 and dendritic spine formation. 40,44 In the adult hippocampus, Wnt5a is required in CA1 neurons to maintain dendritic architecture, and for hippocampal plasticity and spatial learning and memory.…”

“…40,44 In the adult hippocampus, Wnt5a is required in CA1 neurons to maintain dendritic architecture, and for hippocampal plasticity and spatial learning and memory. 39 Here, we determine that through activation of the noncanonical Wnt/CaMKII and Wnt/JNK pathways, Wnt5a regulates neuronal differentiation of progenitor cells, and the development of newborn neurons in the adult dentate gyrus.…”