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.
Schizophrenia is a devastating disorder with a prevalence of about 1% of the population, characterized by positive and negative symptoms and cognitive dysfunction. Patients affected by schizophrenia are treated with antipsychotic drugs, which are effective against positive and negative symptoms, improve the quality of life, and reduce mortality (including the risk of suicide). However, the current treatment of schizophrenia is suboptimal and a significant proportion of patients are resistant to medication. In addition, antipsychotic drugs have negligible effects on cognitive dysfunction and do not restrain the progressive neurodegeneration associated with the disorder. Thus, there is an urgent need for novel pharmacological targets that may help to optimize the treatment of schizophrenia. Recent evidence suggests that abnormalities in the function of cortical interneurons lie at the core of the pathophysiology of schizophrenia (see national and international framing of the project and references therein). Schizophrenia is considered as a neurodevelopmental disorder driven by genetic and epigenetic changes in the developmental trajectory of cortical interneurons. Unraveling the mechanisms that regulate the development of cortical GABAergic interneurons will pave the way to the design of new drugs that may act as disease modifyiers in schizophrenia. Glutamate receptors may have a key role in regulating the development of GABAergic interneurons because glutamate is the neurotransmitter of pyramidal neurons and the maturation and function of interneurons is shaped by their innervation by pyramidal neurons. The project focuses on mGlu5 metabotropic glutamate receptors, which are heavily expressed in the cortex and highly functional in the early stages of postnatal development (postnatal development in rodents corresponds to the last weeks of pregnancy in humans). The project aims at establishing the role played by mGlu5 receptors in four critical processes in the postnatal development of cortical interneurons: (i) the biochemical differentiation of different classes of interneurons; (ii) the developmental switch of GABA-A receptor function from excitatory to inhibitory; (iii) the correct numerical balance between interneurons and pyramidal neurons; and (iv) the formation and degradation of perineuronal nets. The expected findings will move the field beyond the state of the art and will lay the groundwork for future studies aimed at preventing or correcting the pathological phenotype associated with schizophrenia and other psychiatric disorders. Of note, drugs that activate mGlu5 receptors are currently under preclinical development for the treatment of schizophrenia, but they are so far considered as symptomatic drugs on the basis of their antipsychotic-like activity in preclinical models. Our project will explore another potential role of these drugs, which is their impact on a process (the developmental abnormalities of GABAergic interneurons) that is central to the pathological phenotype of patients affected by schizophrenia. Perhaps selective positive allosteric modulators of mGlu5 receptors might be used in the early phases of the natural history of schizophrenia to slow the progression of the disorder and delay or prevent the first episode of psychosis.