The Impact of the Mesoprefrontal System on the Development of Murine Prefrontal Cortex

Abstract

The prefrontal cortex (PFC) is involved in important cognitive processes and undergoes a lengthy functional and anatomical maturation process during postnatal development, which in mammals lasts until early adulthood. Afferent inputs, local microcircuits and the GABAergic interneurons mature during this time, and changes in their development likely contribute to susceptibility to mental illnesses such as schizophrenia. A subset of midbrain dopaminergic neurons (mDA) in the ventral tegmental area (VTA) projects to the PFC, and this so-called mesoprefrontal system modulates the function of the PFC. The development of the mesoprefrontal system is also relatively protracted and correlates temporally with the maturation of the PFC: dopaminergic innervation and dopamine content in the PFC increase strongly during the transition from adolescence to adulthood. This suggests that the appropriate development of mesoprefrontal input may play a key role in the maturation of the PFC microcircuits. To investigate how changes in mesoprefrontal signaling might affect the circuit elements of the PFC, we used a conditional <em>Gli2</em> knockout (cKO) mouse model in which the mDA projections to the PFC are not established. In this model, we followed the development of parvalbumin (PV), calretinin (CR) and calbindin (CB) expressing GABAergic interneurons of the medial (m)PFC and could show that the maturation process of PV and CB interneuron populations was impaired in the mPFC of <em>Gli2</em> cKO animals. In particular, PV interneurons are sensitive to the lack of dopaminergic input in <em>Gli2</em> cKO mice, as they are unable to maintain adequate PV expression during late adolescence and adulthood, which is associated with a concomitant decrease in their Gad1 expression. In <em>Gli2</em> cKO mice, the expression of DA receptor transcripts was also altered during development. However, other monoaminergic innervations were not affected by the absence of mDA projections, as the innervation pattern and density of serotonergic and noradrenergic projections in the mPFC of <em>Gli2</em> cKO mice remained unchanged. To determine the functional impact of impaired mesoprefrontal DA signaling, a spatial working memory task was performed with the <em>Gli2</em>-cKO mice, which revealed that a proportion of <em>Gli2</em> cKO mice have severe deficits in working memory. Our study shows that adolescence is a sensitive period in which the dopaminergic mesoprefrontal input plays a crucial role in the postnatal maturation of specific subsets of interneurons. The results of this study may contribute to a better understanding of the role of a developmentally dysregulated mesoprefrontal system in the pathophysiology of neurodevelopmental disorders.