A single link to the first track to allow the export script to build the search page
  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    059—Mood Disorders: Animal Models I

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    59.23: Behavioral effects of viral mediated deletion of fibroblast growth factor receptor 1 in medial prefrontal cortex

    Location: Halls B-H

    *A. BECKER, M. BANASR, R. S. DUMAN;
    Dept. of Mol. Psychiatry, Yale Univ., New Haven, CT

    Abstract Body: Neurobiological disorders like depression, schizophrenia, autism and anxiety disorders are diagnosed according to their predominant features, although these diseases frequently share overlapping symptoms and genetic markers. Alterations of glial growth factors have been reported in many of these disorders, and are thought to contribute to dysregulation of neuronal survival, neuroplasticity, neurogenesis, and gliogenesis. Recently, fibroblast growth factors (FGFs) have been linked to psychiatric disorders at both the genetic and RNA expression levels by genome wide association studies and microarray analysis. Studies of postmortem tissue from depressed subjects report decreased levels of FGF2 mRNA and increased levels of its high affinity receptor, FGFR1. Conversely, our lab has found that infusion of FGF2 into the medial prefrontal cortex (mPFC) exerts antidepressant properties in rodent models of depression. Given that FGF2 is the primary ligand for FGFR1, we now investigate the influence of a region- specific knockdown of FGFR1 on behavioral and cellular responses related to psychiatric disorders. Local knockdown was achieved by adenoviral delivery of cre recombinase into the mPFC of mice with a conditional null mutation of FGFR1 (FGFR1fl/fl). The influence of FGFR1 knockdown on locomotor activity, anxiety and depression-related behaviors was determined. Region specific knockdown of FGFR1 (FGFR1fl/fl cre) resulted in augmented exploratory behavior in the open field test, which was accompanied by dramatically increased locomotion in the central area of the brightly illuminated arena and elevated rearing in the central area. Furthermore, FGFRf/f cre mice were less immobile (an antidepressant-like respsonse) during the forced swim test, while climbing behavior did not differ between control and FGFRf/f cre mice. We are currently using immunohistochemical approaches to further characterize the cell types and molecular signaling pathways underlying the actions of FGFR1. Together, these studies will elucidate the basic neurobiological actions of FGF2-FGFR1 signaling in relation to depression and anxiety and could enable the development of improved therapeutic treatments for depression and other illnesses.

    Lay Language Summary: Our research indicates that viral mediated deletion of fibroblast growth factor receptor 1 in neuronal cells of the medial prefrontal cortex is sufficient to induce depression-associated behaviors.
    Regulation of cell growth, differentiation and proliferation by growth factors, including fibroblast growth factors (FGFs), are important for normal function and health of an organism. Contrarily, unregulated cell growth with high rates of cell division characterizes cancer and neuronal atrophy and loss of function is a hallmark of neurodegenerative disorders like Alzheimer’s disease and Parkinson.
    Recently, FGFs have been linked to psychiatric disorders by several, large scale screening methods of human samples. Decreased levels of FGF2 mRNA and increased levels of its high affinity receptor (FGFR1) are also reported for postmortem brain tissue of depressed patients. Conversely, our lab found that infusion of FGF2 into the medial prefrontal cortex, a brain region important for decision making, personality expression and orchestrating thoughts, exerts antidepressant properties in rodent models of depression. Given that FGF2 is the primary ligand for FGFR1, we hypothesized that a region- specific knockdown of FGFR1 in the murine medial prefrontal cortex would induce depression-related behaviors.
    We achieved local, cortical loss of FGFR1 by an adeno-associated virus (AAV) that expressed cre recombinase. The viral delivered enzyme recombined a short target sequence flanking the FGFR1 gene of genetically modified mice and consequently erased the genetic FGFR1 information in the transduced cells. Afterwards, mice were tested in anxiety and depression-related tasks and their locomotor activity was determined.
    Region specific loss of FGFR1 by an AAV5 serotype, resulted in augmented exploratory behavior in the open field test, which was accompanied by dramatically increased locomotion in the central area of the brightly illuminated arena and elevated rearing in the central area (features, frequently changed in models of anxiety). Furthermore, these mice were less immobile (an antidepressant-like response) during the forced swim test, while climbing behavior did not differ from controls.
    Different AAV serotypes vary in the coding sequence of their shells and thus in their ability to target specific cell types within a host (tropism). Therefore, we also determined the same behavioral parameters after infusion of the cre enzyme delivered by an AAV2, as this virus nearly exclusively targets neuronal cells.
    Contrarily to the AAV5 treated mice, cortical loss of FGFR1 by AAV2 resulted in a robust depression-associated phenotype. AAV2 treated mice showed less preference for a sweetened dinking solution, a phenomenon known as anhedonia, the inability to experience pleasure and a hallmark of human depression. In addition, these mice were more immobile (a depression-associated response) during the forced swim test, while anxiety and locomotor activity as unaffected in these mice. Interestingly, chronic treatment with the classic, tricyclic antidepressant drug imipramine over several weeks did not alleviate the observed depression-like behavior.
    Taken together our results show that the viral tropism mainly contributes to the observed behavioral modifications and suggest that loss of FGFR1 in neuronal cells of the medial prefrontal cortex is sufficient to induce depression-associated behaviors.
    We are currently using immunohistochemical approaches to further characterize the transfected cell types and molecular signaling pathways underlying the actions of FGFR1. Together, these studies will elucidate the basic neurobiological actions of fibroblast growth factors in relation to depression and anxiety. Our results further suggest that targeting FGFR1 signaling in neuronal cells of the medial prefrontal cortex could provide a new avenue to cure treatment resistant, depressed patients and to improve their quality of life.
    Supported by NIMH Grants MH045481 and MH093897, and the State of CT.