1Epilepsia 2005 -1 46 Suppl 7: 22-8
PMID16201992
TitleDisruption of interneuron development.
AbstractDisruption of gamma-aminobutyric acid (GABAergic) interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences. Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an important molecular cue that may guide the movement of interneurons from their birthplace in the ganglionic eminences (GE) to their final resting place in the neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in pallial and subpallial tissues is associated with a reduction in the number of cells migrating out of GE explants. The uPAR knockout mouse provides a unique opportunity to study the effects of interneuron disruption in vivo. uPAR-/- mice have reduced HGF/SF bioactivity in the GE during the period of interneuron development and a concomitant 50% reduction in the number of GABAergic interneurons seeding frontal and parietal regions of the cerebral cortex. Behaviorally, these mice display an increased susceptibility to seizures, heightened anxiety, and diminished social interaction. This article discusses the commonalities between the functional defects seen in uPAR-/- mice and those of humans with developmental disorders, such as epilepsy, schizophrenia, and autism. It is suggested that disruption of GABAergic interneuron development may represent a common point of convergence underlying the etiologies of many of these developmental disorders.
SCZ Keywordsschizophrenia
2Behav. Brain Res. 2014 Feb 259: 143-51
PMID24211452
TitlePrefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons.
AbstractAlterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition.
SCZ Keywordsschizophrenia