Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

Abstract

During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer’s disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts.

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

“…Activation of canonical WNT signaling is known to regulate the expression of target genes through β-catenin accumulation, nuclear translocation, and binding of β-catenin to DNA-bound members of the TCF/LEF family of High-mobility group (HMG) transcription factors, for example TCF7L2 (RefSeq gene ID 6934; not to be confused with TCF4 itself [32,35,36]). This binding of β-catenin displaces co-repressor complexes that normally prevent gene expression in the absence of WNT pathway activation through epigenetic silencing [37,38].…”

“…In particular, given previous reports in nonneuronal cells of TCF4 being under control of canonical WNT/β-catenin signaling [21,22], we first tested whether different TCF4 transcripts responded to modulation of the canonical WNT signaling pathway as illustrated in Figure 2a. To first stimulate WNT signaling, we tested activation of the pathway at the level of stimulation of the Frizzled family of G-protein-coupled receptors through the secreted glycoprotein Wnt3a, and also by inhibition of GSK3 (glycogen synthase kinase 3), a negative regulator of canonical WNT signaling that phosphorylates β-catenin to promote its ubiquitin-dependent degradation via the destruction complex composed of AXIN/APC (adenomatosis polyposis coli) and PP2A (protein phosphatase 2A)/CK1 (casein kinase 1) [32,33,34]. As a source of Wnt3a that we had already validated as a regulator of canonical WNT signaling in human NPCs, we used Wnt3a conditioned media (Wnt3a-CM [25]).…”

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

“…The Wnt family proteins are secreted growth factors that regulate developmental processes, such as cell fate and polarity and general cell maintenance events, by modulating homeostasis and the cell cycle (1,2). Furthermore, Wnt signaling controls various steps in the differentiation of the central nervous system (3)(4)(5), including axon guidance, dendrite development, synapse formation and plasticity (6,7).…”

Wnt-5a Ligand Modulates Mitochondrial Fission-Fusion in Rat Hippocampal Neurons

“…Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function, and neuronal plasticity and may be reactivated or suppressed in aging or disease (48). In A, CA1 hippocampal slices were treated for until 120 min with Wnt-5a, and p-Drp1(Ser-616) levels were detected by Western blot and normalized to total Drp1 and to the loading control GAPDH (panel a).…”