The Role of Smad2 in Adult Neuroplasticity as Seen through Hippocampal-Dependent Spatial Learning/Memory and Neurogenesis

Abstract

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gainof-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.

Cortical Plasticity is associated with Blood-Brain-Barrier Modulation

“…These results suggest that caveolae albumin transcytosis and TGF-β signaling are key mediators of activity-dependent BBB modulation and subsequent synaptic plasticity. These findings are supported by reports linking TGF-β signaling to: synaptic plasticity induced by environmental enrichment (Dahlmanns et al, 2022); enhanced spine and synapse formation (Patel and Weaver, 2021); and hippocampal neuroplasticity (Gradari et al, 2021). Moreover, our finding of caveolaemediated albumin transcytosis in pial arterioles is in line with previous studies showing: caveolae-dependent transcytosis of albumin (Tecedor et al, 2013); caveolae abundance in arteriolar ECs and not capillary ECs (Chow et al, 2020); and the contribution of caveolae transcytosis to neurovascular coupling (Andreone et al, 2017;Chow et al, 2020).…”

Mechanisms underlying the effect of voluntary running on adult hippocampal neurogenesis

“…Voluntary running also increases spine motility at 21 dpi, which is the peak of spine development (C. Zhao et al, 2006). The stimulation of spine development has also been demonstrated by other independent studies (Eadie et al, 2005;Gradari et al, 2021;Lin et al, 2012;Stranahan et al, 2009;C. Zhao et al, 2014).…”

“…Voluntary running fails to increase neurogenesis in TLX‐null adolescent mice and these mice exhibit reduced neuronal survival compared to wild‐type mice, suggesting that TLX voluntary running‐induced adult neurogenesis relies on the maintenance of adult NSCs by TLX (Kozareva et al, 2018). Gradari et al (2021) has assessed differential DNA methylation of neurogenesis and stem cell‐related transcription factors induced by mildly forced exercise (treadmill) using DNA methylation arrays and identified demethylation of the Smd2 gene, encoding the SMAD2 protein, in the hippocampal tissue of the exercise group. Although this study illustrates importance of SMAD2 in regulating adult neurogenesis through their retrovirus‐mediated gain and loss of functions assays, the necessity of SMAD2 for exercise‐induced neurogenesis is unverified.…”

Effects of Subchronic Propofol Administration on the Proliferation and Differentiation of Neural Stem Cells in Rat Hippocampus

“…The neurogenesis of these NSCs within the hippocampal dentate gyrus plays an important role in learning and memory capacity. 25 A Ki67 antibody was used to evaluate the proliferative activity of NSCs in the adult male rat hippocampal dentate gyrus because Ki67 is known to be expressed in proliferating cells and can be identified throughout the majority of the mitotic cycle. 26 These results suggest that subchronic treatment with 60 mg/kg IP propofol actually may promote NSC proliferation, whereas a higher, 120 mg/kg IP propofol dose inhibited their proliferation.…”