The role of fast-spiking parvalbumin interneurons in prefrontal mediated cognition

Abstract

In a constantly changing environment, the ability to shift from one learned behavioral strategy to another more adaptive strategy is imperative. Research suggests there may be common underlying causes for the similar cognitive etiologies observed in many psychiatric disorders. One of these causes appear to be alterations in cortical GABAergic tone in the prefrontal cortices, particularly in the Orbital Frontal Cortex (OFC) which is known for its role in reversal learning and the Medial Prefrontal Cortex (mPFC) which mediates a form of behavioral flexibility. We tested a mouse model of defective frontal lobe inhibitory GABAergic anatomy on cognitive tasks, including a mouse reversal/set-shift test and fear-conditioning paradigm. We used several lines of mice: a mouse lacking the urokinase plasminogen activator receptor (uPAR) gene with a decreased GABA interneuron phenotype, a hepatocyte growth factor/scatter factor (HGF/SF) overexpressing mouse (Gfap-HGF), and a cross between the uPAR-/- and the Gfap-HGF mice, in which the interneuron deficit appears to be corrected. We have also developed a mouse serial reversal task in which we can record in vivo single unit activity in awake behaving animals, to evaluate murine OFC function during reversal learning. Further, we have studied the role developmental alterations to cortical GABAergic tone play in reversal learning. Using a transgenic animal model to produce a specific frontal cortical GABAergic deficit in adult mice, we have assessed reversal learning through behavioral and in vivo psychological techniques, using single cell and local field potential recordings. By studying genetically altered mice, our research illuminated a common neural substrate between mouse circuitry and behavior and human cortical function in psychiatric disease states. We have shown that mice have functional and dissociable prefrontal cortical structures that match rat, primate and human data. We have shown that GABAergic deficits specific to PV+ interneurons impact prefrontal mediated cognition and that OFC and mPFC cortices are differentially sensitive to growth factor alterations. We further showed that high frequency oscillations are reduced in Plaur mice performing a serial reversal task, and that murine OFC plays a critical role in mediating behavioral flexibility in a first, but not subsequent reversals.