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The Journal of Neuroscience, March 3, 2004, 24(9):2247-2258; doi:10.1523/JNEUROSCI.5285-03.2004

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Development/Plasticity/Repair
Loss of Glutamatergic Pyramidal Neurons in Frontal and Temporal Cortex Resulting from Attenuation of FGFR1 Signaling Is Associated with Spontaneous Hyperactivity in Mice

Dana M. Shin,¹ Sailaja Korada,¹ Rossana Raballo,¹ Cooduvalli S. Shashikant,² Antonio Simeone,⁵ Jane R. Taylor,³ and Flora Vaccarino^1,4

¹Child Study Center, Departments of ²Cellular, Molecular, and Developmental Biology, ³Psychiatry, and ⁴Neurobiology, Yale University, New Haven, Connecticut 06520, and ⁵Medical Research Council, King's College, London SE1 1UL, United Kingdom

Fibroblast growth factor receptor (FGFR) gene products (Fgfr1, Fgfr2, Fgfr3) are widely expressed by embryonic neural progenitor cells throughout the CNS, yet their functional role in cerebral cortical development is still unclear. To understand whether the FGF pathways play a role in cortical development, we attenuated FGFR signaling by expressing a tyrosine kinase domain-deficient Fgfr1 (tFgfr1) gene construct during embryonic brain development. Mice carrying the tFgfr1 transgene under the control of the Otx1 gene promoter have decreased thickness of the cerebral cortex in frontal and temporal areas because of decreased number of pyramidal neurons and disorganization of pyramidal cell dendritic architecture. These alterations may be, in part, attributable to decreased genesis of T-Brain-1-positive early glutamatergic neurons and, in part, to a failure to maintain radial glia fibers in medial prefrontal and temporal areas of the cortical plate. No changes were detected in cortical GABAergic interneurons, including Cajal-Retzius cells or in the basal ganglia. Behaviorally, tFgfr1 transgenic mice displayed spontaneous and persistent locomotor hyperactivity that apparently was not attributable to alterations in subcortical monoaminergic systems, because transgenic animals responded to both amphetamine and guanfacine, an 2A adrenergic receptor agonist. We conclude that FGF tyrosine kinase signaling may be required for the genesis and growth of pyramidal neurons in frontal and temporal cortical areas, and that alterations in cortical development attributable to disrupted FGF signaling are critical for the inhibitory regulation of motor behavior.

Key words: FGFR; fibroblast growth factor; cerebral cortex; pyramidal neuron; radial glia; Tbr1; hyperactivity; proliferation

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Received Sep 15, 2003; revised January 4, 2004; accepted January 5, 2004.

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