Abstract
BackgroundNew neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. However, the molecular mechanisms underlying neuron production and how they are integrated into existing circuits under such physiological conditions remain unclear. Indeed, the intracellular modulators that transduce the extracellular signals are not yet fully understood.ResultsWe show that Smad3, an intracellular molecule involved in the transforming growth factor (TGF)-β signaling cascade, is strongly expressed by granule cells in the dentate gyrus (DG) of adult mice, although the loss of Smad3 in null mutant mice does not affect their survival. Smad3 is also expressed by adult progenitor cells in the subgranular zone (SGZ) and more specifically, it is first expressed by Type 2 cells (intermediate progenitor cells). Its expression persists through the distinct cell stages towards that of the mature neuron. Interestingly, proliferative intermediate progenitor cells die in Smad3 deficiency, which is associated with a large decrease in the production of newborn neurons in Smad3 deficient mice. Smad3 signaling appears to influence adult neurogenesis fulfilling distinct roles in the rostral and mid-caudal regions of the DG. In rostral areas, Smad3 deficiency increases proliferation and promotes the cell cycle exit of undifferentiated progenitor cells. By contrast, Smad3 deficiency impairs the survival of newborn neurons in the mid-caudal region of the DG at early proliferative stages, activating apoptosis of intermediate progenitor cells. Furthermore, long-term potentiation (LTP) after high frequency stimulation (HFS) to the medial perforant path (MPP) was abolished in the DG of Smad3-deficient mice.ConclusionsThese data show that endogenous Smad3 signaling is central to neurogenesis and LTP induction in the adult DG, these being two forms of hippocampal brain plasticity related to learning and memory that decline with aging and as a result of neurological disorders.
Highlights
New neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress
We recently found that Smad3 deficiency, an intracellular molecule involved in Transforming growth factor-β (TGF-β) signaling cascade, promotes nigrostriatal dopaminergic neurodegeneration and α-synuclein aggregation [22]
Through in situ hybridization using a specific probe against Smad3, we found Smad3 transcripts to be strongly expressed in the CA1-CA3, hilus and dentate gyrus (DG) regions of the hippocampus
Summary
New neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. Extracellular signals that regulate survival and integration, such as the neurotrophic factors BDNF, FGF-2 and NT-3 [12,13,14], or the neurotransmitters GABA [12,15,16] and Glutamate [17,18], require intracellular modulators to transduce these signals. In this sense, it has been described the role of Prox in transducing Wnt singaling [19], CREB signaling in GABA-mediated excitation [20] or NFATc4 for BDNFdriven survival signaling [21] in adult hippocampal neurogenesis (AHN)
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