Members of the Lombroso lab study the role of the protein STEP in brain disorders. STEP acts on a number of substrates to oppose synaptic strengthening. In particular, it removes certain subunits of glutamate receptors from synaptic membranes. These receptors are necessary for turning short-term memories into long-term memories. The current model suggests that optimal levels of STEP activity are necessary for proper cognitive function.
Disruption of STEP activity occurs in over a dozen different illnesses. STEP is overactive in fragile X syndrome, schizophrenia, Alzheimer’s disease, and Parkinson’s disease. STEP is underactive in alcoholism, ischemia/stroke, Hunting-ton’s disease, and various forms of drug abuse.
We used a mouse model to test whether countering overactive STEP might reduce the cognitive deficits normally present. Both genetic and pharmacologic reduction of STEP activity in mice with Alzheimer’s disease, fragile X syndrome and schizophrenia reversed the cognitive deficits.
We also cultivated human glutamate-related neurons from patients with schizophrenia, where we showed both elevated STEP activity, and that the inhibition of STEP activity restored the biochemistry, neuron to neuron signaling, and structure of these human cells. These results suggest that inhibiting STEP may have therapeutic benefits in a number of central nervous system disorders. We are identifying additional STEP inhibitors that we hope can be used in clinical trials.
The Lombroso lab is led by Dr. Paul Lombroso, Professor in the Child Study Center, and Departments of Psychiatry and Neuroscience.