Regional differences in dendritic spine morphology and innervation of the trisynaptic circuit of a mouse model of GSK-3β overexpression

Abstract The trisynaptic circuit, which includes the entorhinal cortex (EC), dentate gyrus (DG), and Cornu Ammonis (CA1, CA2, and CA3) of the hippocampus, is among the regions first affected by Alzheimer’s disease (AD). Glycogen synthase kinase-3β (GSK-3β) has emerged as a key enzyme in AD pathology, with potential relevance to synaptic alterations within the trisynaptic circuit. Indeed, a mouse model of AD that overexpresses GSK-3β displays decreased dendritic spine density in the DG. However, the effects of GSK-3β overexpression on the remaining regions of the trisynaptic circuit are still unknown. Here, we analyzed dendritic spine morphology and density in apical and basal dendrites of CA1, CA3, and EC pyramidal neurons in wild-type (WT) and GSK-3β-overexpressing (GSK-3β-OE) mice using intracellular Lucifer Yellow injections. WT mice showed intrinsic differences in spine density and spine-type distribution between apical and basal dendrites across regions. GSK-3β overexpression induced region-specific alterations. The EC showed subtle morphological changes, suggesting partial structural resilience despite its early involvement in AD. The CA3 region presented minimal alterations overall, with basal dendrites being more affected than their apical counterparts, likely due to the differential input they receive. In contrast, CA1 was the most affected region, consistent with its known vulnerability to AD pathology. Finally, a reduced percentage of area occupied by Vesicular glutamate transporter 1 (VGlut1) + boutons in both CA1 and basal CA3 dendrites indicated a loss of excitatory innervation in GSK-3β-OE mice, thereby suggesting disrupted synaptic plasticity. The regional variability in the observed alterations in dendritic spines suggests a selective vulnerability of certain hippocampal areas during the progression of the disease.