Maria Morabito, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Cell Biology

Other Affiliation(s):
   Program in Neuroscience

Regulation of Excitatory Synapses in Development and Disease

An integral component of dendritic spines is the postsynaptic density (PSD), a cytoskeletal structure which organizes the postsynaptic signaling machinery. The PSD is molecularly complex and contains many classes of proteins including adhesion molecules, and scaffolding, cytoskeletal, and signaling proteins. The PSD also contains NMDA and AMPA receptors, two types of glutamate receptors that play critical roles in learning and memory, neurologic and psychiatric disorders. Studies from many laboratories have indicated that dendritic spines and their PSD are dynamic structures that are modified by neuronal activity and in response to LTP and LTD, two forms of synaptic plasticity related to learning and memory.

My lab is interested in understanding the molecular and functional organization of dendritic spines in normal physiological conditions and in identifying alterations associated with synaptic dysfunction. We are using genetic, pharmacological, cellular, molecular, and imaging approaches to gain insight into the postsynaptic networks that regulate NMDA and AMPA receptors signaling and the morphology and stability of dendritic spines.

Current projects in the laboratory:

1. Regulation of NMDA and AMPA receptors postsynaptic signaling
2. Synaptic dysfunction in Alzheimer’s disease
3. Regulation of cytoskeletal dynamics in dendritic spines

	Rat hippocampal neuron in culture (above) expressing b-Gal (to visualize the dendrites) and immunostained for b-Gal (green) and PSD-95 (red), a protein enriched in dendritic spines.
	The postsynaptic density (dark area, above) is a highly organized, dynamic structure that contains NMDA and AMPA receptors (left). We are interested in identifying the molecular mechanisms that regulate NMDA and AMPA receptors signaling and their alterations in neurodegenerative and psychiatric disorders.

Publications

Zhang S., Edelmann L., Liu J., Crandall J.E., Morabito M.A. (2008). Cdk5 Regulates the Phosphorylation of Y1472 NR2B and the Surface Expression of NMDA Receptors. J Neurosci. 28:415-24.

Roselli F., Tirard M., Lu J., Hutzler P., Lamberti P., Livrea P., Morabito M., Almeida O.F. (2005). Soluble beta-amyloid1-40  inducesNMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci. 25:11061-70.

Morabito M.A., Sheng M, Tsai LH. (2004). Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci. 24:865-76.

Patzke H., Maddineni U., 1,2, Ayala R., Morabito M.A., Volker J., Dikkes P., Ahlijanian M.K., and Li-Huei Tsai. (2003) Partial Rescue of the p35 -/- Brain Phenotype by Low Expression of a NSE p25-transgene J Neurosci. 23: 2769-78.

Dhavan R., Greer P., Morabito M.A., Orlando L.R., and Tsai L.-H. (2002) The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner. J Neurosci. 22:7879-91.

Krishnan G, Morabito M.A., and Moczydlowski E. (2001) Expression and characterization of Flag-epitope- and hexahistidine-tagged derivatives of saxiphilin for use in detection and assay of saxitoxin. Toxicon 39: 291-301.

Niethammer M, Smith D.S., Ayala R, Peng J, Ko J, Lee M.S., Morabito M.A., and Tsai L-H., (2000).  NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein.  Neuron 28: 697-711.

Redmond L., Hockfield S., and Morabito M.A. (1996).  The divergent homeobox gene PBX1 is expressed in the postnatal subventricular zone and interneurons of the olfactory bulb.  J. Neuroscience 16: 2972-2982.

Moss G.W.J., Marshall J., and Morabito M.A., Howe J.R., and Moczydlowski E. (1996).  An evolutionary conserved binding site for serine proteinase inhibitors in large conductance calcium-activated potassium channels.  Biochemistry 35: 16024-16035.

Morabito M.A., Llewellyn L.E., and Moczydlowski E. (1995).  Expression of saxiphilin in insect cells and localization of the saxitoxin-binding site to the C-terminal domain homologous to the C-lobe of transferrins.  Biochemistry 34: 13027-13033.

Morabito M.A. and Moczydlowski E. (1994).  Molecular cloning of bullfrog saxiphilin: A unique relative of the transferrin family that binds saxitoxin.  Proc. Natl. Acad. Sci. USA 91: 2478-2482.

Barnstable C.J. and Morabito M.A. (1994).  Isolation and coding sequence of the rat rod opsin gene.  J. Mol. Neurosci. 5: 207-209.

Yu X., Chung M., Morabito M.A. and Barnstable C.J. (1993).  Shared nuclear protein binding sites in the upstream region of the rat opsin gene.  Biochem. Biophys. Res. Commun. 191: 76-82.

Morabito M.A., Yu X., and Barnstable C.J. (1991).  Characterization of developmentally-regulated and retina-specific nuclear protein binding to a site in the upstream region of the rat opsin gene.  J. Biol. Chem. 266: 9667-9672.

Treisman J.E., Morabito M.A., and Barnstable C.J. (1988).  Opsin expression in the rat retina is developmentally regulated by transcriptional activation.  Mol. Cell. Biol. 8: 1570-1579.

Barnstable C.J., Blum A.S., Devoto S.H., Hicks D., Morabito M.A., Sparrow J.R., and Treisman J. (1988).  Cell differentiation and pattern formation in the developing mammalian retina.  Neurosci. Res. 8: S27-S41.

Rotations

Research in our lab is focused on the regulation of glutamatergic synapses in the formation and function of synapses, and their dysfunction in neurological and psychiatric disorders.  Specifically, we are interested in identifying signal transduction pathways that regulate post-synaptic responses and cytoskeletal changes upon synaptic transmission.  We identified a novel mechanism by which the cdk5 kinase regulates glutamatergic synapses.  Cdk5 phosphorylates the postsynaptic scaffolding protein PSD-95 in vivo and thus regulates the clustering of PSD-95 and NMDA receptors at mature synapses (Morabito et al., 2004).

The following projects are available:

1. We are studying the impact that the kinase cdk5 has on the trafficking of PSD-95 in hippocampal neurons in culture.  Students will study the development of synapses in neuronal cultures lacking cdk5 activity by using imaging, cell biological, and molecular techniques. They will carry out time-lapse microscopy to study the movement of GFP-tagged PSD-95 phosphorylation mutants in cultured neurons.
2. We are interested in developing animal models for studying the impact of cdk5-dependent phosphorylation on learning and memory.  Students will develop knock-in mutant mice carrying mutations in phosphorylation sites in genes encoding PSD-95 and the NMDA receptor subunits NR2A.
3. We are investigating molecular mechanisms for NMDA receptor involvement in drug addiction and psychiatric (e.g. Schizophrenia) and neurodegenerative (e.g. Huntington' s) disorders. Students will use cell biological and molecular techniques to identify changes in protein interactions at synapses in paradigms of synaptic dysfunction.

Office: S7-244
Phone: 508 856-2018
E-mail: Maria.Morabito@umassmed.edu
Keywords: Neurobiology, Cell Biology, Signal Transduction

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