Dr. Francis S. Lee Lab
Sample caption.

Projects

Mechanisms of Slitrk5 signaling

Submitted by mas4019 on October 2, 2019 - 12:14pm
Research Description: 

We have identified Slitrk5 as a novel co-receptor for the brain-derived neurotrophic factor (BDNF) receptor, TrkB that regulates ligand-dependent TrkB receptor endocytic trafficking, as well as altering repetitive behaviors. Slitrk5 is a cell surface type I membrane neuronal specific protein, which has been previously shown by our laboratory to alter corticostriatal function but without a specific mechanism. Our studies on Slitrk5 have linked the in vitro studies of synaptogenic and neurotrophic function with higher order in vivo circuit level biological functions in genetically altered mice.

Mechanisms of Slitrk5 signaling

Endocannabinoids and the FAAH polymorphism

Submitted by mas4019 on October 2, 2019 - 12:13pm
Research Description: 

Using a vertically integrated approach in parallel mouse-human studies to we have analyzed a common human genetic variant in the endocannabinoid system, which highlights the capacity to study molecular defects in plasticity genes, and link them to circuit-level and behavioral phenotypes. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. We have shown that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemistry, neurocircuitry, and behavior. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviors. These findings bridge an important translational gap between the mouse and human.

Endocannabinoids and the FAAH polymorphism

Mechanisms of BDNF as a neurotrophic factor

Submitted by mas4019 on October 2, 2019 - 12:13pm
Research Description: 

Through a ”bottom up” approach involving cell biological and genetically altered mouse studies, we consider the molecular basis and in vivo consequences of a common human genetic variant in the growth factor, BDNF. We have previously identified a sorting mechanism involving unique sequence elements in the BDNF prodomain, as well as a sorting protein, sortilin that specifically mediates this trafficking decision to the regulated secretory pathway.  This sortilin-BDNF interaction provides a plausible molecular model of understanding the trafficking defect found in the common human genetic variant BDNF (Val66Met). We have also generated a knock-in mouse containing the BDNF SNP that represents the first example of a human SNP that has been modeled in mice. This was the one of the first animal models to recapitulate the phenotypic effects of a common human polymorphism expressed in the brain. Analyses of this mouse model have elucidated additional phenotypes (increased anxiety, altered fear learning) and have led to these phenotypes being identified in humans.

Mechanisms of BDNF as a neurotrophic factor

The developmental neurobiology of fear learning and memory

Submitted by mas4019 on October 2, 2019 - 12:12pm
Research Description: 

Our laboratory has recently focused on the broad question of developmental onset of anxiety and fear-related behaviors with translational studies related to adolescent anxiety disorders, one of the most prevalent psychiatric disorders. We have identified a new “sensitive period” for fear learning during peri-adolescence in both mouse models and humans. We have also discovered a new form of synaptic plasticity in the hippocampal-prefrontal cortical circuit that underlies this “sensitive period”. Our current studies consider how this heightened plasticity during adolescence contributes to differences in acquiring, expressing and regulating fear behavior. 

The developmental neurobiology of fear learning and memory

Contact Us

Weill Cornell Medicine Dr. Francis S. Lee Lab 1300 York Avenue, Box 244 New York, NY 10065 Phone: (212) 746-5403