Abnormal level of neuronal activity in the prefrontal cortex (PFC) and connected regions is thought to underlie the symptoms of serious neuropsychiatric syndromes, including schizophrenia, autism, Tourette's syndrome and substance abuse disorders. The long- term goal of our research program is to understand how the relative proportions of excitatory and inhibitory cortical neurons are regulated during pre- and post-natal development. Our previous studies have shown that Fibroblast Growth Factor (Fgf) signaling upregulates excitatory cortical neuron number, leading to volume expansion in prefrontal and temporal regions. Pilot data suggest that Fgf receptor 2 (Fgfr2) during embryogenesis increases the number of """"""""intermediate"""""""" progenitors in the SVZ, which in turn is associated with pyramidal neuron genesis in PFC. In contrast, Fgf receptor1 (Fgfr1) is not involved in prenatal cortical development, but may increase the differentiation or survival of cortical parvalbumin+ and somatostatin+ inhibitory interneurons by an action in postnatal glial cells. In this competing continuation proposal, we hypothesize that Fgfr2 signaling in embryogenesis expands the surface area of PFC by stimulating the production of intermediate progenitors in the SVZ from radial glial cells. This will be tested in Specific Aim 1 by tracing the progeny of radial glial cells harboring a deletion of Fgfr2 alleles induced at specific stages of prenatal development. Also, general cortical morphogenesis will be compared amongst mice lacking Fgfr2 versus mice with a combined deletion of Fgfr1, Fgf2 and Fgf3. The effect of Fgf receptor stimulation and blockade upon identified radial glial cells will be also assessed by electroporating dominant negative and dominant active Fgf receptors driven by a specific radial glial promoter.
In specific aim 2 and 3, we will assess whether Fgf signaling in glial cells indirectly promotes the survival or functional maturation of cortical inhibitory neurons expressing Parvalbumin (PV) and Somatostatin (ST) and the developmental time window for this action.
In Aim 2, we will transplant GFP+ wild type interneurons into the postnatal cortex of Fgfr1 mutant mice to determine whether the Fgfr1 mutant cortex is less permissive for interneuron maturation. We will also assess intrinsic firing properties and synaptic integration into the cortical network of the transplanted and endogenous interneurons in Fgfr1 mutant mice.
In specific aim 3, we will specifically inactivate Fgfr1 in GFAP+ cells by virus-induced or temporally regulated recombination of Fgfr1 at either prenatal or postnatal stages of development, and examine interneuron maturation and survival. Together, the experiments will elucidate how specific Fgf receptors may play specific roles in different epochs of life.

Public Health Relevance

Abnormalities in the development of the prefrontal cortex are thought to underlie the symptoms of schizophrenia, autism, attention deficit hyperactivity and drug addiction. This proposal investigates how growth factors of the FGF family establish the primary structure of the cerebral cortex by controlling the genesis of cortical projection neurons from SVZ precursors. The project also focuses on the role of glia in the maturation of inhibitory interneurons during postnatal development of the cerebral cortex. Both aspects may offer promising leads to correct or reverse the excitatory and inhibitory neuron imbalances that are present in the cerebral cortex of neuropsychiatric and impulse control disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Panchision, David M
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Yale University
Schools of Medicine
New Haven
United States
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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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