When citing an abstract from the 2009 Annual - Society for ...

NIH T32 MH018268-24
Solnit Integrated Training Program at Yale Child Study Center
Title: FGFR2 is required in radial glial cells for excitatory neurogenesis in prefrontal cortex and
normal performance on cognitive tasks
Authors: *H. E. STEVENS 1 , K. M. SMITH 2 , M. E. MARAGNOLI 2 , Y. OHKUBO 2 , D.
FAGEL 2 , M. SCHWARTZ 3 , T. HORVATH 4 , F. M. VACCARINO 5 ;
2 3 4 5
Yale Child Study Ctr., Dept. of Neurobio., Dept. of Comparative Med., Child Study Ctr.,
1
Yale Univ. Sch. Med., New Haven, CT
Abstract: FGF ligands (FGF2, FGF8, and FGF17) are expressed in anterior regions of the
developing cerebral cortex and bind FGF receptor 2 (FGFR2) which is expressed in the
ventricular and subventricular zones of the embryonic cortex, particularly in rostral regions. We
generated conditional fgfr1, fgfr2 and double fgfr1/fgfr2 knockout mice lacking FGF receptors in
radial glial cells of the dorsal telencephalon from embryonic day 14 onward, by GFAPCremediated
recombination. Animals were analyzed by stereological morphometric analyses to
determine the number of different cell types in the cerebral cortex and connected subcortical
regions. Mice were also tested in a number of behavioral paradigms.
Embryonic fgfr2 KO mice showed deficits in proliferative cells in the cortical subventricular
zone as well as decreased numbers of TBR2+ neuronal precursors and TBR1+ excitatory
neurons. Adult fgfr2 KO mice had reduced TBR1+ excitatory neuron numbers and cortical
volumes, more marked in medial prefrontal regions. These excitatory neuron deficits were more
marked in fgfr1/fgfr2 KO mice. Inhibitory interneurons of the parvalbumin type were
significantly lower throughout the adult neocortex of mice lacking either fgfr1 or fgfr2. In the
dorsal bed nuclei of the stria terminalis (BST), a projection area for neurons in medial prefrontal
cortex, fewer and smaller glutamate synapses were observed by electron microscopy in fgfr2 KO
mice. Calretinin positive neurons were also deficient in the BST and septum, and this decrease
was correlated in both wildtype and mutant mice with medial prefrontal excitatory neuron
number. Mutant and wildtype mice showed no differences in stress reactivity but demonstrated
locomotor hyperactivity and impairments in object recognition. Mice also showed distinct
patterns of behavior on social approach and anxiety paradigms.
We conclude that FGFR2 signaling in radial glial cells and their progeny is necessary for the
normal development of the anterior regions of the cerebral cortex and its connections within
limbic circuits. Fgfr2 is also required for the development of distinct subtypes of inhibitory
neurons within the neocortex and in the BST and septum, deficits which likely develop
secondarily to the primary alteration in excitatory circuitry. The contribution of FGF to these
neural structures is not essential for their regulation of stress reactivity but does affect motor and
cognitive behavior.
Disclosures: H.E. Stevens, None; K.M. Smith, None; M.E. Maragnoli, None; Y. Ohkubo,
None; D. Fagel, None; M. Schwartz, None; T. Horvath, None; F.M. Vaccarino, None.