Adult-born neurons generated in the dentate gyrus (DG) within the hippocampus participate in specific brain functions, such as learning and memory. After their birth, these adult-born neurons migrate locally within the granule cell layer, mature into granule neurons, and integrate into the existing circuitry. Adult-born neurons have unique functional properties as they mature and can be preferentially activated, thus contributing to specific hippocampal behaviors, including pattern separation. Aberrant maturation or circuit integration of these neurons contributes to cognitive and affective deficits. It has been demonstrated that both intrinsic excitability and synaptic activity of newborn neurons can affect their maturation rate and synaptic integration during this developmental process. Recently, we identified the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of adult-born neuron morphogenesis. We found that TRIM9 is highly expressed in adult hippocampus including newborn neurons, and global deletion of the murine gene encoding TRIM9 caused striking neuronal maturation and integration defects in the adult-born neurons, including aberrant placement of soma, abnormally elevated dendritic arborization, and reduced dendritic spine density. Additionally, TRIM9 deletion was associated with severe spatial learning deficits, a hippocampal dependent behavior involving the contribution from adult-born neurons. Whether TRIM9 functions cell autonomously in adult-born neurons to elicit these phenotypes is unknown. Using conditional TRIM9 knockout mice generated by the Gupton lab, we will test the hypothesis that TRIM9 plays a cell-autonomous role in regulating functional integration and maturation of adult-born neurons, functional connectivity of adult-born neurons to their downstream targets, and hippocampal-dependent learning and memory. The goal of this study is to unequivocally determine how altered maturation and integration of adult-born neurons mediated by cell-autonomous TRIM9 deletion affects hippocampal microcircuit plasticity and impacts hippocampal-dependent behaviors.
Within the dentate gyrus (DG) of adult hippocampus, one of the most striking and yet vulnerable forms of structural plasticity is the ongoing process of neurogenesis throughout life in all mammals including humans. Accumulating evidence suggests that DG new neurons participate in specific brain functions, including learning and memory, stress responses, and mood regulation. Accumulating evidence supports a contribution of dysfunctional postnatal neurogenesis in the manifestation of neurological disorders, characterized by disruptions in cognitive and affective behaviors including emotional regulation and multiple forms of learning and memory. Since adult-born neurons are tractable cells for potential therapeutic intervention, targeting adult- born neurons could be a novel therapeutic strategy for these disorders.
| Bao, Hechen; Song, Juan (2018) Treating Brain Disorders by Targeting Adult Neural Stem Cells. Trends Mol Med 24:991-1006 |
