The proposed investigations focus on the role of Fibroblast Growth Factors (Fgf) receptors on the morphogenesis and function of the cerebral cortex, and particularly frontal regions, whose development is disrupted in schizophrenia. We hypothesize that Fgf receptor 1 (Fgfr-1) play essential roles in inducing or maintaining the specification of neural stem cells to anterior cortical fates and in promoting stem cell expansion within these regions. To test these hypotheses, we will use mice lacking the Fgfr-1 gene product in neuroepithelial cells of the dorsal telencephalon by site-specific recombination (conditional knockout) beginning at either E9.5 or E13.5 stages of development.
Aim 1 will test that Fgfr-1 is necessary to either induce or maintain anterior cortical fates, and that the disruption of this gene produces a """"""""posteriorization"""""""" of the VZ and cortical mantle, as tested by region specific molecular markers.
Aim 2 asks whether Fgfr-1 expands the number of radial glial progenitor cells during cortical development. This will be approached by examining cell proliferation and radial glial markers in the cortical ventricular zone (VZ) in Fgfr-1 recombinant mice and littermate controls, both in vivo and in tissue explants.
Aim 3 analyzes the mechanisms of callosal dysgenesis in Fgfr-1 conditional knockout mice. Tract-tracing experiments will assess the trajectories of long-range neocortical projections in Fgfr-1 recombinant animals as compared to controls. We will test whether Fgfr-1 regulates the expression of receptors for guidance cues by callosal pyramidal neurons or the patterning of midline cellular structures that must be traversed by their axons.
Aim 4 examines whether aberrant cortical development leads to impairments in learning and memory and the inhibitory control of behavior. This question will be approached by testing Fgfr-1 recombinant mice and littermate controls in a battery of sensorimotor and learning tasks. We predict that recombinant mice will show impairments in working memory and will have difficulty in suppressing previously conditioned responses (reversal learning). We further predict that the degree of these impairments will be predicted by the degree of neuronal hypoactivity (as assessed by c-fos immunostaining) within regions of the frontal cortex.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067715-02
Application #
6826236
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Sieber, Beth-Anne
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$367,875
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Salmaso, Natalina; Stevens, Hanna E; McNeill, Jessica et al. (2016) Fibroblast Growth Factor 2 Modulates Hypothalamic Pituitary Axis Activity and Anxiety Behavior Through Glucocorticoid Receptors. Biol Psychiatry 80:479-489
Smith, Karen Müller; Maragnoli, Maria Elisabetta; Phull, Pooja M et al. (2014) Fgfr1 inactivation in the mouse telencephalon results in impaired maturation of interneurons expressing parvalbumin. PLoS One 9:e103696
Salmaso, Natalina; Tomasi, Simone; Vaccarino, Flora M (2014) Neurogenesis and maturation in neonatal brain injury. Clin Perinatol 41:229-39
Rash, Brian G; Tomasi, Simone; Lim, H David et al. (2013) Cortical gyrification induced by fibroblast growth factor 2 in the mouse brain. J Neurosci 33:10802-14
Stevens, Hanna E; Su, Tina; Yanagawa, Yuchio et al. (2013) Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex. Psychoneuroendocrinology 38:509-21
Stevens, Hanna E; Jiang, Ginger Y; Schwartz, Michael L et al. (2012) Learning and memory depend on fibroblast growth factor receptor 2 functioning in hippocampus. Biol Psychiatry 71:1090-8
Stevens, Hanna E; Mariani, Jessica; Coppola, Gianfilippo et al. (2012) Neurobiology meets genomic science: the promise of human-induced pluripotent stem cells. Dev Psychopathol 24:1443-51
Muller Smith, Karen; Williamson, Theresa L; Schwartz, Michael L et al. (2012) Impaired motor coordination and disrupted cerebellar architecture in Fgfr1 and Fgfr2 double knockout mice. Brain Res 1460:12-24
Salmaso, Natalina; Vaccarino, Flora M (2011) Toward a novel endogenous anxiolytic factor, fibroblast growth factor 2. Biol Psychiatry 69:508-9
Rash, Brian G; Lim, H David; Breunig, Joshua J et al. (2011) FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis. J Neurosci 31:15604-17

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