Flora M. Vaccarino, M.D.

Associate Professor, Child Study Center and Department of Neurobiology

Research Interests

In the Child Study Center’s Developmental Neurobiology Laboratory we study how the interaction between genes and adverse prenatal and perinatal events during development cause altered ratios of excitation/inhibition, generating long-term malfunctions of the neuronal network. We believe that an excitatory/inhibitory imbalance in specific forebrain systems due to disparate etiologies can be the common pathogenesis of childhood neuropsychiatric disorders such as Tourette’s syndrome, ADHD and autism. We have shown that in the developing cerebral cortex, genes of Fibroblast Growth Factors (FGF) family are crucial for attaining the proper number of excitatory projection neurons with respect to that of inhibitory interneurons. Gain or loss of function for FGF2 cause increases or decreases, respectively, in the number of cortical pyramidal neurons that are generated during development, without any change in inhibitory neurons. However, conditional loss-of-function for the FGF receptors affects both excitatory and inhibitory neuron types in different proportions, causing long-term repercussions in the animal’s behavior. One of the FGF receptors, FGFR1, is up-regulated in an animal model of perinatal hypoxia, a risk factor for cognitive handicap common in premature children and a predisposing factor for ADHD and Tourette’s syndrome. We discovered that the FGFR1 orchestrates a remarkable attempt at repairing brain injury after hypoxia, with increased production of new excitatory neurons and oligodendrocytes from astroglial neural stem cells. Current projects in our laboratory:

• Genes that promote plasticity in early postnatal development, focusing upon the role astroglial neural stem cells and their capacity to promote brain repair. The role of specific FGFR gene products is investigated by knocking them out in the astroglial cells at specific stages of postnatal development.
• FGF over-expression as a risk factor for autism, using a mouse model of conditional (induced) over-expression of FGF2 during mammalian neurogenesis which is expected to increase excitatory neurons in the cerebral cortex.
• Altered distribution of parvalbumin neurons as a risk factor for ADHD and Tourette syndrome. This project involves stereological analyses of interneurons in the human brain of individuals with Tourette’s syndrome (TS), as well as the analysis cortico-basal ganglia development in a hyperactive mouse model with a specific loss of Parvalbumin inhibitory interneurons. The hypothesis is that the postnatal addition of these inhibitory cells to cortical and basal ganglia circuitry is aberrant in these animals causing specific alterations in synchronous neuronal firing that may model disorders of the ADHD/TS spectrum.

Links

• Vaccarino's Lab

Recent Publications

• Chen, K., Ohkubo, Y., Shin, D., Doetschman, T., Sanford, P.L., Li, H., and Vaccarino, F.M.: Decrease in excitatory neurons, astrocytes and proliferating glial progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene. BMC Neuroscience (2008) 9:94. doi:10.1186/1471-2202-9-94. http://www.biomedcentral.com/1471-2202/9/94
• Fagel DM, Ganat Y, Silbereis J, Ebbitt T, Stewart W, Zhang H, et al. Cortical neurogenesis enhanced by chronic perinatal hypoxia. Exp Neurol 2006;199(1):77-91.
• Fagel, D.M., Silbereis, J., Ohkubo, Y., Ganat, Y., Ment, L.R., Vaccarino, F.M.: Fgfr-1 Is Required For Cortical Regeneration and Repair following Perinatal Hypoxia. Journal of Neuroscience (2009) 29(4):1202-1211.
• Ganat Y, Soni S, Chacon M, Schwartz ML, Vaccarino FM. Chronic hypoxia up-regulates Fibroblast Growth Factor ligands in the perinatal brain and induces Fibroblast Growth Factor -responsive radial glial cells in the sub-ependymal zone. Neuroscience 2002;112(4):977-991.
• Ganat YM, Silbereis J, Cave C, Ngu H, Anderson GM, Ohkubo Y, et al. Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo. Journal of Neuroscience 2006;26(33):8609-21.
• Kalanithi PS, Zheng W, Kataoka Y, DiFiglia M, Grantz H, Saper CB, et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc Natl Acad Sci USA 2005;102(37):13307-12.
• Korada S, Zheng W, Basilico C, Schwartz ML, Vaccarino FM. Fgf2 is necessary for the growth of glutamate projection neurons in the anterior neocortex. Journal of Neuroscience 2002;22:863-875.
• Leckman JF, Vaccarino FM, Kalanithi PS, Rothenberger A. Annotation: Tourette syndrome: a relentless drumbeat--driven by misguided brain oscillations. J Child Psychol Psychiatry 2006;47(6):537-50.
• Muller Smith, K.M., Fagel, D. M., Stevens, H.E., Rabenstein, R.L., Maragnoli, M.E., Ohkubo, Y., Picciotto, M. R., Schwartz, M.L., and Vaccarino, F.M.: Deficiency in Inhibitory Cortical Interneurons Associates with hyperactivity in Fibroblast Growth Factor Receptor 1 Mutant Mice. Biological Psychiatry (2008) 63:953-962.
• Ohkubo Y, Uchida AO, Shin D, Partanen J, Vaccarino FM. Fibroblast growth factor receptor 1 is required for the proliferation of hippocampal progenitor cells and for hippocampal growth in mouse. Journal of Neuroscience 2004;24(27):6057-69.
• Raballo R, Rhee J, Lyn-Cook R, Leckman JF, Schwartz ML, Vaccarino FM. Basic Fibroblast Growth Factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex. Journal of Neuroscience 2000;20(13):5012-5023.
• Shin DM, Korada S, Raballo R, Shashikant CS, Simeone A, Taylor JR, et al. Loss of glutamatergic pyramidal neurons in frontal and temporal cortex resulting from attenuation of FGFR1 signaling is associated with spontaneous hyperactivity in mice. Journal of Neuroscience 2004;24(9):2247-58.
• Smith KM, Ohkubo Y, Maragnoli ME, Rasin MR, Schwartz ML, Sestan N, et al. Midline radial glia translocation and corpus callosum formation require FGF signaling. Nat Neurosci 2006;9(6):787-97.
• Vaccarino FM, Ganat Y, Zhang Y, Zheng W. Stem cells in neurodevelopment and plasticity. Neuropsychopharmacology 2001;25:806-815.
• Vaccarino FM, Ment LR. Injury and repair in developing brain. Arch Dis Child Fetal Neonatal Ed 2004;89(3):F190-2.
• Vaccarino FM, Schwartz ML, Raballo R, Rhee J, Lyn-Cook R. Fibroblast Growth Factor signaling regulates growth and morphogenesis at multiple steps during brain development. In: Pedersen RA, Shatten G, editors. Current Topics in Developmental Biology. San Diego, CA: Academic Press; 1999. p. 179-200.
• Vaccarino FM, Schwartz ML, Raballo R, Nilsen J, Rhee J, Zhou M, et al. Changes in cerebral cortex size are governed by Fibroblast Growth Factor during embryogenesis. Nature Neuroscience 1999;2:246-253.
• Vaccarino, F. M., Smith, K.M., Stevens, H.: Regulation of cerebral cortical size and neuron number by Fibroblast Growth Factors: Implication for autism. Journal of Autism and Developmental Disorders (2009) 39:511-520.
• Zheng W, Nowakowski RS, Vaccarino FM. Fibroblast growth factor 2 is required for maintaining the neural stem cell pool in the mouse brain subventricular zone. Dev Neurosci 2004;26(2-4):181-96.

Contact

Campus Address
Child Study Center
230 South Frontage Road
P.O. Box 207900
New Haven, CT 06520-7900

Office Address
SHM I-266

E-mail
flora.vaccarino@yale.edu

Office Phone
203-737-4147

Fax
203-785-7611