Wnt5a is essential for dendrite maintenance and cognitive functions in the adult brain

Long-term structural maintenance of neuronal networks is essential for sustaining brain functions. The size and pattern of dendrite arbors dictate the ability of neurons to receive and integrate synaptic inputs and are thus critical determinants of information processing in the brain. Established during embryonic and postnatal development, dendrite arbors and many dedritic spines are largely stable in adulthood and are maintained for the lifetime of an organism. Late-onset retraction of dendritic arbors and spine loss are the most consistent morphological correlatlations of common neurological disorders including schizophrenia, chronic stress, anxiety and Alzheimer’s disease. Molecular signals that sustain neuronal morphology and synaptic connectivity in the adult nervous system, however, remain largely unknown. Wnts are secreted glycoproteins that have critical and evolutionarily conserved functions during embryonic development. In the nervous system, Wnt5a has emerged, among the 19 vertebrate Wnts, as a critical regulator of neuronal morphogenesis and synapse formation during development. Interestingly, I found that in the mouse hippocampus, a brain structure critical for the learning and memory, the onset of Wnt5a expression occurs only postnatally. Owing to the early neonatal lethality and global developmental defects in conventional Wnt5a mutant mice, the functions of Wnt5a in the postnatal brain are poorly understood. Using Wnt5a conditioanl knockout mouse model, I investigated the functions of Wnt5a in the adult hippocampus. I reveal an essential role for Wnt5a in maintaining dendrite morphology in the adult hippocampus. Neuron-specific deletion of Wnt5a in mice does not compromise dendrite development in CA1 hippocampal pyramidal neurons, but results in striking adult-onset defects in dendrite arborization, total dendritic lengths and spine densities that manifest after 3 months of age in mice. Electrophysiological analyses revealed impaired synaptic plasticity that preceded the onset of structural alterations in dendrites. Notably, adult Wnt5a mutant animals showed defects in cognitive functions that progressively declined with the manifestation of structural abnormalities. Furthermore, biochemical analyses showed attenuated signaling of key components of calcium and planar cell polarity pathways, and a decrease in CREB-mediated transcription of the obligatory NMDA receptor subunit, GluN1, in the mature Wnt5a mutant hippocampus. These molecular changes could underlie the cognitive and structral abnormalities due to the loss of Wnt5a. Together, this study provide the first direct in vivo evidence that Wnt5a is essential for maintenance of neuronal connectivity and for cognitive functions and provide insight into neuroprotective mechanisms in the adult brain