Learning and memory depend upon changes in synaptic connections in response to neuronal activity and this is termed synaptic plasticity. Long-lasting forms of synaptic plasticity depend upon new protein synthesis and transcription. The process by which certain stimuli can lead to specific changes in protein synthesis is largely unknown. Brain-derived neurotrophic factor (BDNF) is important for long-term information storage and signaling through various pathways leads to enhanced synaptic transmission. The mechanism by which BDNF selectively promotes the synthesis of a distinct class of proteins was largely unknown until a recent discovery by out lab indicating that this process depends upon regulation of the microRNA biogenesis pathway by BDNF. A long-term objective in this study is to uncover the molecular mechanisms responsible for BDNF-induced regulation of microRNA biogenesis through Lin28a in producing specific changes in new protein synthesis and to determine whether this phenomenon can occur locally at synaptic sites. BDNF is important for the development and proper maintenance of synaptic connections. BDNF is also implicated in various psychiatric disorders, including major depression, bipolar disorder, and schizophrenia. Therefore, understanding BDNF signaling can help lead to the discovery of novel therapeutic agents important for psychiatric disease and cognitive disorders. Methods of this study include biochemical and genetic approaches to probe the BDNF signaling cascade using a murine model system. In addition, confocal microscopy will be used to study the effects of BDNF treatment on the subcellular distribution of key microRNA biogenesis regulators as well as the localization of microRNAs in cultured hippocampal neurons. These experiments will contribute to a fundamental understanding of the molecular mechanisms of learning and memory, cognitive function, and brain disease. ! The following specific aims will be addressed: 1) Investigate the mechanisms underlying upregulation of the microRNA processing factor, Lin28, by BDNF;2) Determine whether Lin28 levels can be locally controlled at synapses.
The knowledge gained from this research will create a better understanding of the neurotrophic signaling cascades responsible for translation regulation of plasticity-related genes and the role of microRNA biogenesis in this process. These mechanisms are of fundamental neurological consequence for brain plasticity and repair and are hypothesized to underlie the cellular substrate for learning and memory. In addition, it is the aim of these investigations to shed light on how pathways of synaptic plasticity as regulated by the RNA binding protein and pluripotency factor, Lin28a, could operate in both normal brain function as well as in mental health disorders and to provide potential targets for diagnosing and treating brain disease.
| 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 |
| Ruiz, Claudia R; Shi, Jay; Meffert, Mollie K (2014) Transcript specificity in BDNF-regulated protein synthesis. Neuropharmacology 76 Pt C:657-63 |
