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Psychiatry & Behavioral Science

Division of Neurobiology

Division of Neurobiology

Director: Christopher A. Ross, M.D., Ph.D.
Co-Director: Russell L. Margolis, M.D.

To contact the Division office, please call Adriana Fonseca at 443-287-4962.

The Division of Neurobiology has the ultimate goal of understanding the neurobiology of psychiatric diseases and translating that understanding into effective clinical treatments. It currently comprises basic science labs of six faculty members, as well as clinical research and services in Huntington's disease. The Division has close associations with clinical and genetic research programs n schizophrenia and with imaging research programs directed at a variety of diseases. We apply modern techniques of molecular biology and genetics to the study of normal brain functioning and neuropsychiatric disorders. We are committed to applying interdisciplinary approaches in order to understand and find effective treatments for diseases affecting the brain. Some of the diseases we study include Huntingtons disease, Parkinsons disease, bipolar disorder, and schizophrenia.

Research Laboratories

The laboratories in the Division use methods ranging from cellular and molecular to systems and behavior. Thus a problem in any disease area can be approached from a multidisciplinary standpoint with a wide range of expertise available. People in different labs are encouraged to collaborate and bring together their unique approaches to problems and to reach out to investigators in other programs and departments, both basic and clinical. Ultimately, the goal is to elucidate the basic biology of brain disorders and to develop biomarkers and novel therapeutic approaches that can be brought to human clinical trials.

Three core beliefs underlie research in the Division of Neurobiology.

  • First, the most effective research is highly interdisciplinary. Division faculty labs use approaches ranging from basic biochemistry and biophysics, to cell biology and mouse genetics to preclinical and clinical therapeutic trials.
  • Second, the powerful techniques of molecular and cell biology that are being used so successfully to unravel the basic biology of neurodegenerative diseases can now be applied productively to schizophrenia and other complex psychiatric diseases. Study of the rare familial forms of neuropsychiatric diseases is likely to illuminate the biology of the more common, apparently sporadic forms of these diseases.
  • Finally, we believe in a translational orientation with the goal of developing biomarkers and experimental therapeutics that can be brought to clinical trials with patients.

The Huntington's Disease Model

The work in Huntington’s disease has provided a model to approach psychiatric diseases. Expansion of a CAG repeat in the huntingtin gene causes expansion of a polyglutamine stretch in the huntingtin protein, altering its structure, and causing cell toxicity and neuronal degeneration. We conducted some of the first studies to identify the abnormal huntingtin protein and to determine toxic mechanisms. We have also identified novel genes causing HD-like diseases. We created some of the first cell models of HD, and used them to screen for compounds which can block toxicity. We generated a transgenic mouse model of HD, which has helped to elucidate pathogenesis and is now one of the models used for preclinical therapeutic studies. Studies of the huntingtin protein contributed to the identification of the neuronal intranuclear inclusions which are the pathologic hallmark of the disease and which have begun to define an aggregation pathway. We contributed to the discovery that huntingtin interferes with gene transcription. This is now one of the major therapeutic strategies being tested in clinical trials of patients. Current studies focus on proteolytic modifications including proteolytic cleavage of huntingtin, aggregation gene transcription, and other cellular events leading to toxicity. Preclinical studies include testing therapeutics in cell and mouse models. We also study the disease closely related to HD termed HDL2. See the labs of Drs. Duan, Margolis, and Ross.

Parkinson's Disease

We have used similar techniques to approach Parkinson’s disease (PD). We studied the protein interaction partners of alpha-synuclein, the protein product of a gene mutated in familial PD. We identified an interaction between alpha-synuclein and protein we termed synphilin-1 and later showed that synphilin-1 interacts with another PD gene product termed parkin. We generated cell models expressing mutant alpha-synuclein and yielding cell death in culture. More recently, we have begun studies of the newly identified Parkinson’s disease gene termed LRRK2. We found that LRRK2 interacts with other PD-related gene products including synphilin-1 and parkin in cells in culture. We have also found that LRRK2 causes robust neuronal degeneration in cells and culture. Furthermore, we have found that kinase activity of LRRK2 is involved in cell toxicity, suggesting therapeutic targets. Current studies focus on mechanisms of alpha-synuclein aggregation and toxicity, cell and mouse models using LRRK2, biomarker identification, and preclinical therapeutics. See the labs of Drs. Smith, Duan, and Ross.

Schizophrenia

Similar techniques are now being used to study schizophrenia. Unlike the degenerative diseases, schizophrenia is believed to be caused by abnormal neurodevelopment. The schizophrenia candidate gene DISC-1 is mutated in a familial form of schizophrenia. DISC-1 interacts with a number of proteins implicated in neuronal development and mutations of DISC1 interfere with neuronal differentiation and development both in vitro and in vivo. We are currently generating and studying cell and mouse models using mutant DISC-1 and other candidate genes and developing models based on gene-environment interactions. We are also searching for novel genetic causes of schizophrenia. See the labs of Drs. Margolis and Ross.

Neuroimaging

Faculty collaborate with research being done by the Division of Psychiatric Neuroimaging on a number of disorders, especially Huntington's disease.

Training Opportunities

We have a range of educational and training programs including a fellowship training program, contributions to residency training, and opportunities for graduate and post-graduate researchers. Techniques used in the basic science labs include molecular biology, cell biology, biochemistry, and cell and mouse models of disease. Clinical research on Huntington's disease, cerebellar and related disorders involves neuropsychiatric evaluation, neuropsychological testing, neuroimaging, and clinical trials of experimental therapeutics.

Neurobiology Division Faculty