We use biochemical, molecular, immunocytochemical, and behavioral techniques in animal models to address the role that STEP plays in regulating aspects of learning.
Current projects include the involvement of STEP in three disorders: Alzheimer's disease, fragile X syndrome, and schizophrenia.
We are characterizing the STEP knock-out mouse, STEP's regulation of local protein translation, STEP's regulation of glutamate receptor trafficking, as well as screening for STEP inhibitors that are tested in animal models to determine if we can rescue cognitive deficits.
There are currently 4 million individuals suffering from Alzheimer's disease (AD) in the USA, with an annual cost of over $200 billion per year. Although some drugs are currently available to treat AD, none provide more than temporary relief from the relentless progression of cognitive deficits. The discovery of new drugs that improve cognitive function is a critically important area in translational research in AD.
Fragile X syndrome is a developmental disorder that is one of the translational neuroscience projects in the lab. FXS is due to transcriptional silencing of Fmr1 gene that encodes Fragile X mental retardation protein (FMRP). FMRP acts as a translation repressor to some synaptic proteins, while mutation of Fmr1 gene can lead to increased translation of these proteins.
Schizophrenia is another disorder in which STEP61 levels are elevated and is a major focus of the current work in the laboratory. The project began under the leadership of Dr. Nikisha Carty (currently at Evotec Pharmaceuticals). Dr. Carty found that STEP61 levels were elevated in dorsal lateral prefrontal cortex and cingulate from two different SZ cohorts and in a phencyclidine model of SZ (Carty et al., 2012). The increase in STEP61 expression was correlated with a decrease in the Tyr phosphorylation of several substrates (e.g., ERK1/2 and GluN2B) and a loss of GluN1/GluN2B complexes from synaptoneurosome membranes.
Over the past decade, I have invited experts in the field of neuroscience to write a series of articles that were published in the Journal of the American Academy of Child and Adolescent Psychiatry. The goal of these columns was to provide the readership with an opportunity to share the excitement of neuroscience relevant to child development and psychopathology.