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Sabina Berretta, MD


Sabina Berretta, MD


McLean Hospital


McLean Hospital Mental Health Research Scholars


2000 - 2002; 2004 - 2005

For nearly 30 years, the funding provided by the Rappaport Foundation to physicians and researchers has allowed brilliance to flourish and breakthroughs to triumph in the areas of neurologic diseases and mental illness.

Sabina Berretta, MD, began her research training under the mentorship of Dr. V. Perciavalle at University of Catania, Italy. In 1990, she joined the laboratory directed by Dr. A. M. Graybiel in the Department of Brain and Cognitive Sciences at MIT, working neural circuitry linking the motor cortex to basal ganglia. In 1997, Dr. Berretta moved to McLean Hospital and Harvard Medical School to work in the laboratory directed by Dr. F. Benes. There she developed an animal model designed to investigate GABAergic abnormalities in schizophrenia.

In 1999, Dr. Berretta became the director of the Translational Neuroscience Laboratory at McLean Hospital. Her investigations are focused on the pathophysiology of major psychoses, testing the hypothesis that extracellular matrix abnormalities may represent a core feature of the pathology of these disorders. In 2014, Dr. Berretta became the scientific director of the Harvard Brain Tissue Resource Center and is now the director.

In addition to her role as scientific director of the Harvard Brain Tissue Resource Center at McLean Hospital, Dr. Berretta is also director of the Translational Neuroscience Laboratory, founded in 2000 to focus on psychotic disorders.

Every cell in the human brain is surrounded by a lattice of molecules called the extracellular matrix. This matrix regulates how brain cells migrate, mature, and connect. Dr. Berretta’s group recently found pronounced abnormalities of this matrix in the brains of people with schizophrenia. Those abnormalities might play a fundamental role in the causes or expression of this condition.

Dr. Berretta’s ongoing work aims to further characterize these and other matrix anomalies in schizophrenia and bipolar disorder, and shed light on related brain mechanisms. Understanding these processes is critical for developing new treatments for psychotic conditions.

Investigations into interconnected brain regions involved in emotion and cognitive processing—such as the amygdala, entorhinal cortex, olfactory system, and limbic thalamus—are designed to test specific hypotheses on molecular and cellular abnormalities in these disorders. 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.

Dr. Berretta’s approach includes studies on postmortem human tissue, complemented by in vitro investigations, each designed to test 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. In vitro studies on human cell cultures are used to assess the validity of pathophysiological molecular mechanisms suggested by postmortem investigations.

Recent findings from Dr. Berretta’s research show marked abnormalities affecting one of the main components of the brain extracellular matrix, i.e., chondroitin sulfate proteoglycans (CSPGs), within the amygdala, entorhinal cortex, and olfactory epithelium of subjects with schizophrenia and—perhaps to a lesser extent—bipolar disorder.

These findings are particularly intriguing, as they point to dysregulation of CSPG secretion and/or metabolism in astrocytes and altered CSPG content in the extracellular matrix. The biological relevance of CSPGs to the pathophysiology of schizophrenia and the magnitude of the changes observed suggest a pivotal—and thus far unsuspected—role for extracellular matrix abnormalities in this disease.

Current investigations predominantly focus on these latter findings, testing hypotheses on the molecular mechanisms, cells, and brain regions involved and interactions with other brain abnormalities in major psychoses.