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The Journal of Neuroscience, January 15, 2003, 23(2):622-631
Genetic Disruption of Cortical Interneuron Development Causes
Region- and GABA Cell Type-Specific Deficits, Epilepsy, and Behavioral
Dysfunction
Elizabeth M.
Powell1,
Daniel B.
Campbell2, 3,
Gregg D.
Stanwood2, 3,
Caleb
Davis4,
Jeffrey L.
Noebels4, and
Pat
Levitt2, 3
1 Departments of Pathology and Neurobiology, University
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, 2 Department of Pharmacology, Vanderbilt University School
of Medicine, Nashville, Tennessee 37232, 3 John F. Kennedy
Center for Research on Human Development, Vanderbilt University,
Nashville, Tennessee 37203, and 4 Blue Bird Circle
Developmental Neurogenetics Laboratory, Department of Neurology, Baylor
College of Medicine, Houston, Texas 77030
The generation of properly functioning circuits during brain
development requires precise timing of cell migration and
differentiation. Disruptions in the developmental plan may lead to
neurological and psychiatric disorders. Neocortical circuits rely on
inhibitory GABAergic interneurons, the majority of which migrate from
subcortical sources. We have shown that the pleiotropic molecule
hepatocyte growth factor/scatter factor (HGF/SF) mediates interneuron
migration. Mice with a targeted mutation of the gene encoding urokinase
plasminogen activator receptor (uPAR), a key component in HGF/SF
activation and function, have decreased levels of HGF/SF and a 50%
reduction in neocortical GABAergic interneurons at embryonic and
perinatal ages. Disruption of interneuron development leads to early
lethality in most models. Thus, the long-term consequences of such
perturbations are unknown. Mice of the
uPAR / strain survive
until adulthood, and behavior testing demonstrates that they have an
increased anxiety state. The
uPAR/ strain also
exhibits spontaneous seizure activity and higher susceptibility to
pharmacologically induced convulsions. The neocortex of the adult
uPAR/ mouse exhibits a
dramatic region- and subtype-specific decrease in GABA-immunoreactive
interneurons. Anterior cingulate and parietal cortical areas contain
50% fewer GABAergic interneurons compared with wild-type littermates.
However, interneuron numbers in piriform and visual cortical areas do
not differ from those of normal mice. Characterization of interneuron
subpopulations reveals a near complete loss of the parvalbumin subtype,
with other subclasses remaining intact. These data demonstrate that a
single gene mutation can selectively alter the development of cortical
interneurons in a region- and cell subtype-specific manner, with
deficits leading to long-lasting changes in circuit organization and behavior.
Key words:
GABA; interneuron; epilepsy; anxiety; urokinase; plasminogen; calbindin; calretinin; somatostatin; parvalbumin; knock-out mouse; neocortex; uPAR
Copyright © 2003 Society for Neuroscience 0270-6474/03/232622-10$05.00/0
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