Alzheimer disease-like cellular phenotype of newborn granule neurons can be reversed in GSK-3β-overexpressing mice

Abstract

In the dentate gyrus of wild-type (wt) mice (a), neuronal precursors maturate and differentiate into mature granule neurons under the influence of pro-neurogenic molecules, such as neurotrophic factors and anti-inflammatory cytokines. In glycogen synthase kinase 3 (GSK-3b)-overexpressing mice (GSK-3b-OE mice) (b), increased neuronal death activates microglia and increases pro-inflammatory cytokine (affecting early neuronal precursor development, as an indirect consequence of GSK-3b overexpression). Throughout the maturational process, morphological alterations are observed in granule neurons of GSK-3b-OE mice. In addition, as a direct consequence of GSK-3b-OE, these cells experience a dramatic reduction of postsynaptic cluster number and volume. Doxycycline treatment did not produce any significant effect on wt mice (c), whereas it successfully reverted the aberrant morphology of granule neurons and normalized pro-inflammatory cytokine levels in GSK-3b-OE mice (d). In addition, the restoration of normal levels of GSK-3b activity produced a drastic increase in the number of postsynaptic clusters (d). The number of postsynaptic clusters is drastically increased in wt mice after environmental enrichment (EE) (e). It is important to note that, in wt mice, EE particularly increased the number of small, newly developed, synaptic contacts, whereas postsynaptic cluster size was increased in GSK-3b-OE animals after EE (f), potentially contributing to enhanced synaptic strength. Interestingly, both doxycycline treatment and EE restored the increased number of ‘pathological’ microglial cells and also normalized pro-inflammatory cytokines to basal levels in GSK-3b-OE mice, thus allowing newborn neurons to develop appropriate morphology and connectivity.