Maria Morabito, Ph.D.

Academic Role: Professor

Faculty Appointments In:
   Cell Biology

Other UMass Program Affiliations:
   Shriver Center
   Program in Neuroscience

Regulation of Excitatory Synapses in Development and Disease

We are interested in understanding how brain function is regulated and what are the molecular basis of brain disorders. Our research aims at identifying molecular mechanisms that regulate signaling between neurons and how they become disregulated in diseased states.

Neuronal circuits are formed during development and can undergo modifications throughout adulthood, for example in response to learning and memory.  The basic unit of neuronal circuitry and site of contact between neurons is the synapse. In the mammalian CNS, excitatory synaptic inputs are received by dendritic spines which are dynamic neuronal structures that are crucial in the regulation of synaptic transmission.  An integral component of the dendritic spine is the postsynaptic density (PSD), a cytoskeletal structure thought to organize the postsynaptic signaling machinery.  The PSD contains NMDA and AMPA receptors, two subtypes of glutamate receptors that associate with various intracellular protein complexes regulating receptors activity and distribution.

In active neurons, neurotransmitters are released at synapses where they bind to and activate specific receptors of the postsynaptic neuron.   The efficacy of this interneuronal communication is constantly being adapted in response to neuronal activity, and this synaptic plasticity is critical for learning and memory. The characterization of the protein interactions underlying these events is essential to gain insight into synaptic communication. 

We are interested in protein-protein interactions and signaling pathways that regulate synaptic function and dysfunction, using imaging, biochemical, and genetic approaches. A major focus of the laboratory is the identification of the molecular mechanisms that integrate structural changes with signaling at excitatory synapses. Specifically, we are interested in the mechanisms that regulate NMDA receptors signaling, since these glutamate receptors play a major role in learning and memory.

Synaptic dysfunction and dendritic spines abnormalities have been implicated in a number of developmental, psychiatric, and neurodegenerative disorders such as Autism, Schizophrenia, and  Huntington ’s. We are using genetic, pharmacological, cellular, and molecular approaches including confocal time-lapse imaging (to monitor the trafficking of synaptic proteins in live CNS neurons) and primary neuronal cultures to identify molecular and cellular synaptic alterations underlying synaptic dysfunction in pathological conditions.

	Rat hippocampal neuron in culture expressing -Gal to visualize the dendrites, and immunostained for -Gal (green) and PSD-95 (red), a protein enriched in postsynaptic structures, the dendritic spines.
	The postsynaptic density is a highly organized, dynamic structure. We are interested in identifying the molecular mechanisms that integrate NMDA receptor signaling with the cytoskeleton

Current projects in the laboratory:

1. Phosphorylation -dependent regulation of post-synaptic structures
2. The reelin pathway in synaptic function and schizophrenia
3. The role of huntingtin at synapses and in glutamate-mediated excitotoxicity

Publications

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.

Academic Background

Ph.D., University of Rome, Italy, 1979

Office: Shriver - 316A
Phone: 781-642-0036 or 642 0291
E-mail: Maria.Morabito@umassmed.edu
Keywords: Neurobiology, Cell Biology, Signal Transduction