Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.

TitleGenetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction.
Publication TypeJournal Article
Year of Publication2003
AuthorsPowell, EM, Campbell, DB, Stanwood, GD, Davis, C, Noebels, JL, Levitt, P
JournalJ Neurosci
Volume23
Issue2
Pagination622-31
Date Published2003 Jan 15
ISSN1529-2401
KeywordsAnimals, Anxiety, Behavior, Animal, Calcium-Binding Proteins, Cell Count, Darkness, Electroencephalography, Epilepsy, Exploratory Behavior, GABA Antagonists, gamma-Aminobutyric Acid, Genetic Predisposition to Disease, Interneurons, Light, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neocortex, Receptors, Cell Surface, Receptors, Urokinase Plasminogen Activator, Spatial Behavior
Abstract

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.

Alternate JournalJ. Neurosci.
PubMed ID12533622
Grant List29709 / / PHS HHS / United States
HD 97-003 / HD / NICHD NIH HHS / United States
MH12651 / MH / NIMH NIH HHS / United States
MH65299 / MH / NIMH NIH HHS / United States