Ricerc@Sapienza

Abnormalities in the developmental trajectories of cortical GABAergic interneurons contribute to the pathophysiology of schizophrenia and other psychiatric disorders. Unraveling the mechanisms that regulate the development of interneurons may lay the groundwork for the identification of new drug targets for the treatment of psychiatric disorders. Here, we focus on mGlu5 metabotropic glutamate receptors, which are highly expressed and functional in the early postnatal life, when cortical interneurons acquire their biochemical and functional phenotype in rodents. We will study the role of mGlu5 receptors in four developmental processes: (i) the expression of specific biochemical markers of different types of cortical interneurons (e.g., parvalbumin, cholecystokinin, somatostatin, vasoactive intestinal peptide, reelin, etc.); (ii) the molecular mechanism (PTEN inhibition) that sculpts cortical networks by regulating the numeric balance between cortical interneurons and pyramidal neurons; (iii) the developmental switch of GABA-A receptor function driven by the expression of the chloride transporter, KCC2, in neurons; and (iv) the formation and degradation of perineuronal nets, which surround parvalbumin-positive interneurons and restrain their plasticity during critical time windows of cortical development. As a model, we will use (i) mGlu5 receptor knockout mice and their wild-type littermates; (ii) normal mice treated with mGlu5 receptor ligands from postnatal days 3 to 8; and (iii) mice subjected to perinatal stress, i.e. the offspring of dams exposed to restraint stress during pregnancy. The analysis will be carried out in the prefrontal cortex at postnatal days 9, 15, and 30, and will combine q-PCR and immunoblot analysis, inmmunohistochemical analysis, in vivo assessment of mGlu5 receptor signaling, stereological cell counting of parvalbumin-positive interneurons, and electrophysiological analysis of cortical GABAergic neurotransmission.