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.
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