Creating a New Window to Study Synaptic (Dys)Function in Brain and Behavior Disorders

Creating a New Window to Study Synaptic (Dys)Function in Brain and Behavior Disorders

Posted: August 7, 2012

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Zhiping Pang, Ph.D., Assistant Professor of Neuroscience and Cell Biology at UMDNJ-RWJMS-Child Health Institute of New Jersey won the 2012 Freedman Prize on July 27, 2012 for his development of a novel way to study synaptic dysfunction in brain and behavior disorders, including schizophrenia and bipolar disorder. The Freedman Prize honors the late Daniel X. Freedman, M.D., a pioneer in biological psychiatry and psychopharmacology and a founding member of the Brain & Behavior Research Foundation Scientific Council. It is presented annually to a NARSAD Young Investigator Grantee for exceptional basic research.

Dr. Pang’s research is focused on discovering the mechanisms of the regulation of synaptic transmission in the central nervous system and how deficits in synaptic function lead to brain and behavior disorders, including schizophrenia, bipolar disorder and eating disorders that lead to obesity. Building upon the recent advances in stem cell biology, and particularly the work showing that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a minimum of four transcription factors, Dr. Pang and colleagues hypothesized that neuronal lineage-specific transcription factors could go a step further to directly convert fibroblasts into functional neurons.

With the support of the 2008 NARSAD Young Investigator Grant, they used candidate screening to define a minimum of three to four factors that suffice to rapidly and efficiently convert mouse and human embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. The iN cells, if derived from patients directly, can be used to study cellular and molecular mechanisms that might be involved in the pathogenesis of brain and behavior disorders that are very difficult to identify in living humans. The study was published in Nature (August, 2011)

Brain function relies on information flow from one neuron to another, a process that primarily takes place in specialized structures called synapses. Research has demonstrated that dysfunction in synaptic transmissions leads to brain and behavior disorders. Synaptic transmission is tightly regulated by calcium ions; nerve firing induces calcium influx and triggers synaptic vesicle exocytosis. Dr. Pang has spent a number of years researching how calcium exquisitely regulates synaptic transmission through calcium-binding proteins such as synaptotagmins and SNARE proteins. Understanding the molecular mechanism of synaptic release is crucial to elucidating how the brain functions, and to understanding how it can dysfunction.

This new work with iN cells from non-neural-lineage human cells may provide a completely new window for studying neural development, modeling neurological disease and furthering regenerative medicine. Dr. Pang hopes to harness the potential of the cell-based model to develop more effective treatment of the diverse symptoms related to synaptic dysfunction in brain and behavior disorders.

Dr. Pang says that the support of his NARSAD Young Investigator Grant was critical to pursuing this ‘out of the box’ work. He says: “While traditional funding agencies normally refrain from high-risk/high-reward ventures, the Brain & Behavior Research Foundation provided me the opportunity to pursue research in a novel area and thus served as the impetus to realize ambitious neuroscience research goals.”

In 2011, Dr. Pang was awarded a second NARSAD Young Investigator Grant to study the synaptic mechanism of food intake in the central nervous system. This is important because a major symptom of mood disorders is abnormal eating behavior and a major side effect of many atypical antipsychotic agents is the development of obesity and type II diabetes. The understanding of the neural basis of feeding behavior is of great relevance to the treatment of many of the major mental illnesses.