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MAILMAN RESEARCH CENTER

Laboratory for Translational Neuroscience

Parvalbumin-expressing neurons in the human amygdala represent a subpopulation of GABAergic interneurons
 
Confocal photomicrographs
 
Glial cells expressing condroitin sulfate proteoglycans (CSPGs)

Images by the Laboratory for Translational Neuroscience (click to enlarge)


Research in the Translational Neuroscience Laboratory, established in 2000, focuses on the pathophysiology of major psychoses. Investigations on interconnected brain regions involved in emotion and cognitive processing, such as the amygdala, entorhinal cortex, olfactory system, limbic thalamus and orbitofrontal cortex, are designed to test specific hypotheses on molecular and cellular abnormalities in these disorders. We place particular emphasis on comparisons between schizophrenia and bipolar disorder.Genetic, clinical, pharmacological and pathological observations strongly suggest broad overlap, as well as key differences, between these disorders. Thus, parallel investigations on the pathophysiology of schizophrenia and bipolar disorder may represent a powerful tool to shed light on the mechanisms underlying the clinical domains attributed to both or either of these disorders. By increasing our knowledge on the specific pathophysiological mechanisms at the basis of schizophrenia and bipolar disorder,researchers in this laboratory hope to contribute to a deeper understanding of major psychoses and improvement of medical treatment.

Our approach includes studies on postmortem human tissue, animal models, and more recently, in vitro preparations, each designed to investigate complementary aspects of the pathophysiological mechanisms of schizophrenia and bipolar disorder. Postmortem investigations on human brain tissue are essential to test hypotheses on molecular and cellular abnormalities affecting interacting neuronal, glial and extracellular matrix systems within distinct brain regions in each of these disorders. Animal models are designed to simulate such abnormalities in a living system in order to test their causes and mechanisms at the system level. The developmental maturation of neural components affected, and presence of critical time periods during which specific changes are required to occur in order to cause a pathology equivalent to that detected during adulthood, are also an important aspect of these animal models. In vitro studies on human cell cultures are used to assess the validity of pathophysiological molecular mechanisms suggested by postmortem investigations.

Recent findings from our group show that the amygdala and the entorhinal cortex are involved in both schizophrenia and bipolar disorder and that, within these regions, overlapping cell populations are affected.Yet, our results also point to key differences with regard to cellular and molecular aspects as well as pathophysiological mechanisms. For instance, the amygdala, selective reductions of the total number of neurons and volume of the lateral nucleus were detected in subjects with bipolar disorder, but not schizophrenia. In the entorhinal cortex, total numbers of neurons expressing the calcium binding protein parvalbumin were found to be decreased in bipolar disorder patients. No significant changes were detected in subjects with schizophrenia, with the exception of a cell size decrease restricted to the intermediate subdivision. However, in schizophrenia but not bipolar disorder, recent findings show marked abnormalities affecting one of the main components of the brain extracellular matrix, i.e. chondroitin sulfate proteoglycans (CSPGs), within the amygdala and entorhinal cortex. These findings are particularly intriguing, as they point to schizophrenia-specific disregulation of CSPG secretion and/or metabolism in astrocytes and altered CSPG content in the extracellular matrix. Interestingly, parvalbumin-positive neurons in the entorhinal cortex are one of the main neuronal populations likely to be affected by these changes. Thus, these neurons may be affected in both schizophrenia and bipolar disorder, although the causes and functional consequences of their abnormalities are fundamentally different. The biological relevance of CSPGs to the pathophysiology of schizophrenia and the magnitude of the changes observed suggest a pivotal, thus far unsuspected, role for extracellular matrix abnormalities in this disease. Current investigations in our group are predominantly focusing on these latter findings, testing hypotheses on the molecular mechanisms, cells and brain regions involved and interactions with other brain abnormalities in schizophrenia.

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03.2012