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Highlights: [•] Loss of Plaur leads to reduced numbers of medial frontal cortical interneurons. [•] Excess HGF/SF increases hippocampal and medial frontal cortical interneurons. [•] Amygdalar interneurons are not affected by Plaur loss or excess HGF/SF. [•] Fear extinction and attentional set formation are dependent on interneuron number. [ABSTRACT FROM AUTHOR]

Abstract: The ability to learn a rule to guide behavior is crucial for cognition and executive function. However, in a constantly changing environment, flexibility in terms of learning and changing rules is paramount. Research suggests there may be common underlying causes for the similar rule learning impairments observed in many psychiatric disorders. One of these common anatomical manifestations involves deficits to the GABAergic system, particularly in the frontal cerebral cortical regions. Many common anti-epileptic drugs and mood stabilizers activate the GABA system with the reported adverse side effects of cognitive dysfunction. The mouse reversal/set-shifting test was used to evaluate effects in mice given topiramate, which is reported to impair attention in humans. Here we report that in mice topiramate prevents formation of the attentional set, but does not alter reversal learning. Differences in the GABA system are also found in many neuropsychiatric disorders that are more common in males, including schizophrenia and autism. Initial findings with the reversal/set-shifting task excluded female subjects. In this study, female mice tested on the standard reversal/set-shifting task showed similar reversal learning, but were not able to form the attentional set. The behavioral paradigm was modified and when presented with sufficient discrimination tasks, female mice performed the same as male mice, requiring the same number of trials to reach criterion and form the attentional set. The notable difference was that female mice had an extended latency to complete the trials for all discriminations. In summary, the reversal/set-shifting test can be used to screen for cognitive effects of potential therapeutic compounds in both male and female mice. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a complex developmental disorder that presents challenges to modern neuroscience in terms of discovering etiology and aiding in effective treatment of afflicted humans. One approach is to divide the constellation of symptoms of human neuropsychiatric disorders into discrete units for study. Multiple animal models are used to study brain ontogeny, response to psychoactive compounds, substrates of defined behaviors. Frontal cortical areas have been found to have abnormal anatomy and neurotransmitter levels in postmortem brains from schizophrenic patients. The mouse model has the advantage of rather straightforward genetic manipulation and offers numerous genetic variations within the same species. However, until recently, the behavioral analyses in the mice lagged behind the primate and rat, especially with respect to testing of frontal cortical regions. Current reports of mouse prefrontal anatomy and function advocate the mouse as a feasible animal model to study prefrontal cortical function. This review highlights the most recent developments from behavioral paradigms for testing orbital and medial prefrontal cortical function in pharmacological and genetic models of human schizophrenia. This article is part of a special issue entitled ‘Schizophrenia’. [Copyright &y& Elsevier]

Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors. [ABSTRACT FROM AUTHOR]

Abstract: Disrupted ontogeny of forebrain inhibitory interneurons leads to neurological disorders, including epilepsy. Adult mice lacking the urokinase plasminogen activator receptor (Plaur) have decreased numbers of neocortical GABAergic interneurons and spontaneous seizures, attributed to a reduction of hepatocyte growth factor/scatter factor (HGF/SF). We report that by increasing endogenous HGF/SF concentration in the postnatal Plaur null mouse brain maintains the interneuron populations in the adult, reverses the seizure behavior and stabilizes the spontaneous electroencephalogram activity. The perinatal intervention provides a pathway to reverse potential birth defects and ameliorate seizures in the adult. [Copyright &y& Elsevier]