Synaptic plasticity, regarded as the cellular correlate of learning and memory, involves a selective strengthening and weakening of synapses in response to neuronal activity. Changes in gene expression combined with novel protein synthesis have long been recognized as necessary for lasting changes in synaptic connections. However, surprising recent studies have shown that regulation at the level of transcription is not necessarily correlated with regulation at the level of translation, and thus that the profile of mRNA in a cell is only moderately correlated with the proteome. Brain-derived neurotrophic factor (BDNF) is a crucial regulator of long-lasting changes in synaptic connectivity. It plays an important role in consolidation of learning and memory, and is misregulated in a wide range of neurologic and cognitive disorders including mood disorders, anxiety disorders, and Schizophrenia as well as neurodegenerative disease. Interestingly, BDNF enhances the expression of an extraordinarily specific subset (about 4%) of transcribed mRNAs by regulating components of the microRNA biogenesis pathway. One important aspect of this regulation is the induction of a protein called Lin28a, which is a pluripotency factor that inhibits biogenesis of specific microRNAs and was thought previously to be absent from mature cell types such as neurons. The first goal of the proposed research is to understand the molecular mechanisms and signaling pathways through which BDNF enhances Lin28a protein, thus regulating gene expression. Understanding such mechanisms involved in the BDNF signaling pathway has the potential to uncover regulatory points that could be the target of future therapeutics. Experiments in this section will require molecular, biochemical, and genetic approaches to analyze BDNF signaling outcomes in cultured mouse hippocampal neurons. Additionally, the second goal of the proposed research is to enhance and repress activity of Lin28a protein in in vitro and in vivo neuronal systems. Analysis of cell morphological and behavioral readouts following these manipulations will directly indicate how BDNF-mediated induction of Lin28a protein may impact neuronal structure as well as cognitive function. These experiments have the potential to directly suggest therapeutic agents for cognitive and neurologic disorders. Methods in this section will include immunohistochemistry, fixed cell imaging and analysis, and assessment of hippocampal-based learning tasks in wild type and genetically manipulated mice. Overall, the proposed experiments will enhance our current knowledge of the molecular mechanisms that underlie learning and memory normally and that may be dysregulated in diseases and disorders of the brain.
Regulation of gene expression in the central nervous system is crucial for the cellular processes that modulate synaptic connectivity and underlie learning and memory. This research aims to understand how neurons control and achieve specificity in gene expression, using brain-derived neurotrophic factor (BDNF) as a model system. BDNF signaling is crucial for normal brain function and is dysregulated in numerous cognitive and psychiatric diseases, thus the proposed research has the potential to generate therapeutic targets for such brain disorders. .
| Amen, Alexandra M; Ruiz-Garzon, Claudia R; Shi, Jay et al. (2017) A Rapid Induction Mechanism for Lin28a in Trophic Responses. Mol Cell 65:490-503.e7 |
