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

MININI C.; DI GUILMI, M.; MARIN-BURGIN, A.; TOMASELLA, M.E.; BECHELLI, M.L.; ELGOYHEN, B.; OGANDO M.; ZANUTTO, S.; GELMAN, D.M

San Diego

Congreso; Society for Neuroscience Annual Meeting; 2016

Socienty for Neuroscience

Schizophrenia is a complex neurodevelopmental diseasecaused by both genetic and environmental factors. It is characterized by aheterogeneous collection of symptoms including altered perception, decreasedmotivation, and cognitive deficits. The dopaminergic hypothesis of the diseaseis the most enduring, as pharmacological treatment is based on antagonism ofdopamine 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 theGABAergic hypothesis. Besides this, the glutamatergic hypothesis ofschizophrenia has emerged based on reports showing that inhibition of NMDA(N-Methyl D-aspartate) receptors causes behavioral responses similar to thepositive and cognitive symptoms observed in patients. Although great advances havebeen made in the last decades, and evidence supports each of the hypotheses, themolecular mechanisms leading to schizophrenia are still to be elucidated.Moreover, antipsychotics are the only treatment, with benefits just forpositive symptoms, but limited results for negative or cognitive ones. As DRD2is expressed in PV interneurons, the aim of the present work was to evaluate towhat extent FSI inhibitory control over pyramidal neurons was modulated by DRD2.With this objective, we generated a conditional mutant mice line, by deletionof DRD2 specifically in PV+ interneurons. We first determined the mRNA expressionlevel of many genes, as GAD 67, highly related to the pathophysiology of thisdisease. Our results showed a significant reduction in the mRNA of this andother relevant genes in the prefrontal cortex and hippocampus in conditionalmutants compared to controls. Electrophysiological approach showed neuronal andnetwork perturbations in conditional mutants, but not in control animals. We thenfollowed a battery of behavioral tests to analyze the consequences of thisdeletion, focusing on locomotor activity, emotional and social behavior andcognitive function. Our results showed an alteration in total locomotoractivity, impairments in cognitive capacity and deficits in social andemotional behavior in conditional mutants but not in control mice. In summary, our results show that deletion of DRD2 from FSI causesbiochemical and physiological unbalances with functional consequences inbehavior, suggesting that DRD2 exerts a fine tuning role in the development ofa balanced activity in PV interneurons and, consequently, in the neuronalnetwork.