Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

Abstract

Alterations 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.

Keywords: Attentional set; Cued extinction; EDS; GABA; HGF; HGF/SF; IDS; ID–ED; ID–ED shift; MFC; Morris water maze; OFC; PCR; PV; Plaur; SEM; Urokinase plasminogen activator receptor; extradimensional shift; gamma-aminobutyric acid; gene for hepatocyte growth factor/scatter factor; gene that encodes urokinase plasminogen activator receptor; hepatocyte growth factor/scatter factor; intradimensional shift; intradimensional–extradimensional (shift); medial frontal cortex; orbital frontal cortex; parvalbumin; polymerase chain reaction; standard error of the mean.