Consequences of dopamine D2 receptor ablation on fast-spiking interneurons in mice

M. E. TOMASELLA; C. MININNI; M. OGANDO; B. S. ZANUTTO

San Diego

Congreso; Neuroscience 2016; 2016

Schizophrenia is a complex neurodevelopmental disease caused by both genetic and environmental factors. It is characterized by a heterogeneous collection of symptoms including altered perception, decreased motivation, and cognitive deficits. The dopaminergic hypothesis of the disease is the most enduring, as pharmacological treatment is based on antagonism of dopamine D2 receptors (DRD2). Strong evidence also demonstrate that Parvalbumin-expressing (PV), fast-spiking interneurons (FSI) have a central role in the pathophysiology of this disease, supporting the GABAergic hypothesis. Besides this, the glutamatergic hypothesis of schizophrenia has emerged based on reports showing that inhibition of NMDA (N-Methyl D-aspartate) receptors causes behavioral responses similar to the positive and cognitive symptoms observed in patients. Although great advances have been made in the last decades, and evidence supports each of the hypotheses, the molecular mechanisms leading to schizophrenia are still to be elucidated. Moreover, antipsychotics are the only treatment, with benefits just for positive symptoms, but limited results for negative or cognitive ones. As DRD2 is expressed in PV interneurons, the aim of the present work was to evaluate to what extent FSI inhibitory control over pyramidal neurons was modulated by DRD2. With this objective, we generated a conditional mutant mice line, by deletion of DRD2 specifically in PV+ interneurons. We first determined the mRNA expression level of many genes, as GAD 67, highly related to the pathophysiology of this disease. Our results showed a significant reduction in the mRNA of this and other relevant genes in the prefrontal cortex and hippocampus in conditional mutants compared to controls. Electrophysiological approach showed neuronal and network perturbations in conditional mutants, but not in control animals. We then followed a battery of behavioral tests to analyze the consequences of this deletion, focusing on locomotor activity, emotional and social behavior and cognitive function. Our results showed an alteration in total locomotor activity, impairments in cognitive capacity and deficits in social and emotional behavior in conditional mutants but not in control mice. In summary, our results show that deletion of DRD2 from FSI causes biochemical and physiological unbalances with functional consequences in behavior, suggesting that DRD2 exerts a fine tuning role in the development of a balanced activity in PV interneurons and, consequently, in the neuronal network.