Despite strong progress in unveiling the elements that confer genetic predisposition for schizophrenia and a wealth of brain imaging data that has allowed identifying critical brain regions that are affected in this disorder, we are still far from a clear view on its pathophysiological mechanisms. The prefrontal cortex, the temporal lobe, amygdala and basal ganglia are known to be involved. Also, several transmitter systems, including dopamine, glutamate and GABA, have been implicated. Indeed, animal models have relied on a number of developmental manipulations, including a lesion in the hippocampus. An important question that remains to be solved is why (and how) early developmental/genetic factors can yield a condition in which symptoms emerge late in adolescence or in early adulthood. We plan to follow recent studies indicating that the actions of dopamine in the prefrontal cortex, in particular on interneurons, mature during adolescence. We will explore the cellular and synaptic mechanisms that may be responsible for this delayed maturation in naove animals, and we will extend those studies to a developmental animal model of schizophrenia. Rats with a neonatal lesion of the ventral hippocampus exhibit abnormal behaviors and cognitive deficits that resemble phenomena observed in schizophrenia. We have also shown that the electrophysiological response to dopamine activation is abnormal in those animals. Despite having the lesion at early ages, all these changes emerge during adolescence;thus, this model is well suited to study delayed emergence of physiological anomalies. We will assess the maturation of prefrontal cortical interneurons in the period between the lesion and the onset of symptoms, and the mechanisms involved in the abnormal responses to dopamine that emerge during adolescence. We will also test whether a pharmacological model (blocking NMDA receptors) exerts its actions by selectively targeting interneurons. The experiments proposed here may open new avenues to think about schizophrenia pathophysiology and brain maturation. New ideas for therapeutic approaches, for example, may emerge from these studies.
This project is aimed at determining whether alterations in prefrontal cortical interneurons are a common element in different animal models of schizophrenia. As interneurons have been repeatedly suggested to be abnormal in post-mortem studies, identifying a) whether they are abnormal in animal models, and b) the nature of those anomalies, has a great potential to provide information that could shape new views on pathophysiological mechanisms in this devastating disorder. The periadolescent maturation of the dopamine modulation of this cell population we reported recently is likely to be affected in these models;if the overall hypothesis in this application is correct, studying this late maturation could provide unique opportunities to design novel therapeutic approaches that target GABA and glutamate transmission in the prefrontal cortex.
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