Identification of approved drugs for BDNF insufficiency

About This Grant

Summary Brain-derived neurotrophic factor (BDNF) exerts its biological actions mainly through TrkB receptors. BDNF-TrkB signaling plays a crucial role in regulating the development and function of neural circuits. BDNF impacts nearly all stages of neural circuit development by promoting neuronal differentiation, axonal and dendritic growth, synapse formation and maturation, and refinement of neuronal connection. In mature neural circuits, BDNF enhances the efficacy of glutamatergic synapses but weaken the efficacy of GABAergic synapses by changing either activity-induced presynaptic transmitter release or postsynaptic responses. BDNF can also alter the capacity of synapses to express activity-induced long-term potentiation or long-term depression. More recently, substantial evidence has established a crucial role for BDNF in the control of energy balance. Mutations in either the Bdnf gene or the Ntrk2 gene that encodes TrkB cause severe obesity in mice and humans. Given these important roles of BDNF in the nervous system, it is not surprising that hyperphagia, severe obesity, intellectual disability, autism, and impaired nociception are observed in approximately 50% of people with WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation) syndrome, due to contiguous gene deletion extended into the BDNF gene, leading to BDNF haploinsufficiency. Thus, a drug that can increase BDNF expression has potentials for treating a subset of WAGR patients with BDNF insufficiency. We have generated a new mouse strain, BdnfNLuc, in which the DNA sequence encoding the highly active nano luciferase (NLuc) was inserted into the Bdnf locus immediately before the stop codon. By using cortical and hippocampal neurons from BdnfNLuc/+ embryos, we developed a highly sensitive and highly reproducible phenotypic assay for detection of BDNF expression in 384-well plates. We had successfully scaled up the assay and performed a pilot screen of the 1280-compound library of pharmacologically active compounds (LOPAC). These results indicate that our assay is ready for high throughput screening. We propose to screen a collection of approved drugs (~4100 compounds) to identify a drug that can increase BDNF expression in both mouse and human neurons in vitro as well as in mice in vivo. We will then determine if administration of the drug can correct several phenotypes observed in Bdnf+/- mice. Findings from these studies could be quickly translated to therapeutic applications for patients with BDNF insufficiency, including the subset of WAGR patients with BDNF deletion. Finally, to find novel chemical structures that may be better suited or more active in increasing BDNF expression, we will screen 20,000 CNS-focused compounds. We aim to find 1-2 lead compounds that can increase BDNF expression in cultured mouse and human neurons and in the mouse brain for future drug development.