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

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 gain-of-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.SIGNIFICANCE STATEMENT Smad2 is one of the main components of the transforming growth factor-β (TGF-β) pathway. The commitment of cell fate in the nervous system is tightly coordinated by SMAD2 signaling, as are further differentiation steps (e.g., dendrite and axon growth, myelination, and synapse formation). However, there are no studies that have directly evaluated the role of Smad2 gene in hippocampus of adult animals. Modulation of these parameters in the adult hippocampus can affect hippocampal-dependent behaviors, which may shed light on the mechanisms that regulate adult neurogenesis and behavior. We demonstrate here a role for Smad2 in the maturation of differentiating immature cells and in the plasticity of mature neurons. Moreover, Smad2 silencing specifically compromises the spatial learning abilities of adult male mice.