Paul J Lombroso MD

Elizabeth Mears and House Jameson Professor in the Child Study Center and Professor of Neurobiology and of Psychiatry; Director, Laboratory of Molecular Neurobiology

Research Interests

Child and adolescent psychiatry; Neuropharmacology

Current Projects

  • Use of dominant negative STEP proteins to disrupt various learning paradigms.
  • Characterization of the STEP knock-out mouse.
  • Regulation of glutamate receptor trafficking by STEP.
  • Role of STEP in Alzheimer’s disease, Fragile X syndrome and schizophrenia.
  • Regulation of local protein translation.
  • Phosphorylation of STEP and function of phosphorylation at specific sites.
  • Characterization of major vault protein.

Research Summary

The laboratory focuses on mammalian learning and how these processes are disrupted in various neuropsychiatric disorders. We are interested in several disorders including fragile X syndrome, schizophrenia and Alzheimer's disease. Central to this investigation is a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.

Our earlier work showed that STEP regulates ERK1/2 and Fyn by dephosphorylating and inactivating them. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors and leads to their internalization. Signals that lead to STEP inactivation potentiate learning, whereas signals that lead to the STEP activation oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques in animal models to address the role that STEP plays in regulating aspects of learning.

On-going projects include the involvement of STEP in three disorders: Fragile X syndrome, Alzheimer's disease and schizophrenia. We are characterizing the STEP knock-out mouse; STEP's regulation of glutamate receptor trafficking; as well as screen for STEP inhibitors that are being tested in various animal models to determine if we can rescue cognitive deficits.

Extensive Research Description

The Lombroso Lab studies how we normally learn and how these processes are disrupted in various neuropsychiatric disorders. We are interested in a number of disorders including Tourette’s syndrome, obsessive-compulsive disorder, autism, as well as drug addiction and Alzheimer’s disease. Our work focuses on a brain-specific protein tyrosine phosphatase called STEP and its role in regulating intracellular signaling.

Studies have shown that STEP regulates ERK1/2 and Fyn by dephosphorylating and inactivating them. STEP also regulates the cell surface expression of AMPA and NMDA glutamate receptors, and leads to their endocytosis. Signals that lead to the inactivation of STEP potentiate learning, while signals that lead to the activation of STEP oppose the development of synaptic plasticity. We use biochemical, molecular, immunocytochemical, and behavioral techniques to address the role that STEP plays in regulating aspects of learning.


Selected Publications

  • Chiodi V, Mallozzi C, Fan Chen J, Ferrante A, Lombroso PJ, Di Stasi AM, Domenici MR, Popoli P (in press) Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP. Neuropsychopharmacology. 39:569-578 PMCID3895235
  • Baguley TD, Xu HC, Chatterjee M, Lombroso PJ, Ellman J (2013) Substrate-based fragment identification for the development of selective, nonpeptidic inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase. J Med Chem 56:7636-7650. PMCID in progress.
  • Deb I, Manhas N, Poddar R, Allan AM, Rajagopal S, Lombroso PJ, Rosenberg GA, Jalil EC, Paul S (2013) Neuroprotective role of STEP, a brain-enriched tyrosine phosphatase, in focal cerebral ischemia. J Neuroscience 33:17814-17826. PMCID3818554.
  • Carty NC, Xu J, Kurup P, Goebel-Goody SM, Brouillette J, Austin DR, Yuan P, Chen P, Chen G, Correa PR, Pittenger C, Lombroso PJ (2012) The tyrosine phosphatase STEP: Implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Translational Psychiatry 2:e137 doi:10.1038/tp.2012. 63. PMCID3410627.
  • Gladding CM, Sepers MD, Xu J, Zhang LY, Milnerwood AJ, Lombroso PJ, Raymond LA (2012) Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington’s disease mouse model. Human Molecular Genetics 21:3739-52 PMCID3412376
  • Sergienko E, Xu J, Liu WE, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford ND, Chung TD, Mustelin T, Page R, Lombroso PJ, Tautz L (2012) A specific inhibitor of hematopoietic protein tyrosine phosphatase augments ERK and p38 activation in vivo. ACS Chem Biol 7:367-377 PMCID3288537.
  • Venkitaramani DV, Moura PJ, Picciotto MR, Lombroso PJ (2011) Striatal-Enriched protein tyrosine Phosphatase (STEP) knockout mice have enhanced hippocampal memory. Eur J Neurosci. 33:2288-2298. PMCID3118976.
  • Hicklin TR, Wu PH, Radcliffe RA, Freund RK, Goebel SM, Proctor WR, Lombroso PJ, Browning MD (2011) STriatal Enriched protein tyrosine Phosphatase (STEP) mediates ethanol inhibition of NMDA receptor activity at hippocampal glutamatergic synapses. PNAS 108:6650-6655. PMCID3081035.
  • Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas J, Lombroso PJ, Alberch J, Pérez-Navarro E (2011) STEP expression and activity in Huntington’s disease-a STEP in the resistance to excitotoxicity. J Neuroscience 31:8150-8162. PMCID3472648.
  • Zhang YF, Kurup P, Xu J, Carty N, Fernandez S, Nygaard HB, Pittenger C, Greengard P, Strittmatter S, Nairn AC and Lombroso PJ (2010) Genetic reduction of STEP reverses cognitive and cellular deficits in a mouse model of Alzheimer’s disease. PNAS.

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