Balice-Gordon Lab
Projects
Lab Projects
Mechanisms of synaptic competition at developing neuromuscular synapses
We are studying the mechanisms underlying synaptic competition during neural development, using neuromuscular synapses as a model system. Using transgenic mice in which the dynamics of synaptic vesicle recycling and trafficking can be monitored in vivo, we are testing the hypothesis that activity modulates presynaptic vesicle recycling and trafficking, affecting synaptic structure, strength and survival.The results of these experiments will provide fundamentally new insights into mechanisms by which activity changes synaptic function and neural circuitry during normal development, and contribute to understanding of developmental disorders such as epilepsy, autism and mental retardation. Click here for more details.
Mechanisms of neuron-astrocyte signaling underlying synapse formation and function
We are studying the mechanisms by which astrocytes modulate inhibitory synapse formation and function in the developing central nervous system. Previous work and preliminary studies in hippocampal neurons in vitro suggest that astrocytes release soluble signals into the media (astrocyte conditioned media, ACM) that increase inhibitory neuron axon elongation, branching as well as synaptogenesis, by the criteria of increasing the number of GABAergic presynaptic terminals colocalized with postsynaptic GABAAR clusters (Elmariah et al., 2004; 2005; Hughes et al., in preparation). These data lead to the hypothesis that secreted signals from astrocytes mediate the formationn of inhibitory synapses during neural development. The results of these experiments will extend our understanding of how inhibitory synapses are formed during neural development, and may also contribute to understanding of disorders of development such as epilepsy, autism and mental retardation. Click here for more details.
Related collaborative projects
Novel forms of encephalitis was recently identified by Dr. Josep Dalmau in the Dept. of Neurology, Penn SOM. These diseases are associated with antibodies to theNR1 subunit of the N-methyl-D-aspartate (NMDA) receptor or the GluR1 / GluR2 subunits of the AMPA receptor. These disorders were initially identified in young women with ovarian teratoma who presented with psychosis or memory problems that evolved to severe complications requiring prolonged intensive care support. Prompt recognition of this disorder is important because patients often improve with treatment.
With Dr. Dalmau and his lab, we are working to study the binding of patients’ antibodies to NMDA or AMPA receptor clusters at synapses formed in cultures of rodent hippocampal neurons. We are also determining how cerebrospinal fluid from affected patients affects synapse structure and function, how NMDA receptors are cleared from synapses, and whether these affects are reversible. Collaborative efforts are underway to generate and characterize animal models of this human disease.
Felix Lab
Zebrafish have become increasingly popular for studying blood cell development because many zebrafish orthologs of blood-specific genes have been identified, and the rapid, external development of abundant, transparent embryos enables real-time functional observations unlike other models. Moreover, transgenic zebrafish models of other leukemias have yielded phenotypes that recapitulate leukemia in humans. In collaboration with Dr. Carolyn Felix and her lab, we are using zebrafish model to understand the role of the human mll gene in normal and malignant hematopoiesis. The mll gene at chromosome band 11q23 is an important oncogene that is disrupted by chromosomal translocations with more than 50 partner genes in infant leukemias and secondary leukemias after chemotherapeutic topoisomerase II poisons. The functions of MLL in normal blood cell development and leukemia are poorly understood. Mll encodes a complex transcription factor that undergoes taspase1 proteolytic cleavage into amino and carboxyl fragments that re-associate in a multiprotein complex and regulate expression of HOX genes, cell cycle genes and other unknown targets. Experiments in mice indicate that MLL is important for normal hematopoiesis and that disruption of MLL function is leukemogenic. We have cloned a complete zebrafish mll cDNA, and have shown that mll depletion in zebrafish embryos leads to blood cell defects and neuronal cell death, resembling phenotypes observed in Mll-/- mice. Understanding the role of mll in hematopoeisis in zebrafish as a model system will provide a rapid screening tool to test anti-leukemic agents targeting MLL fusion proteins or their downstream effectors.
Holzbaur Lab
The microtubule motor protein cytoplasmic dynein and its activator dynactin are essential in all mammalian cells, due to critical roles in both mitosis and intracellular trafficking. However, motor neurons are uniquely sensitive to defects in dynein or dynactin. Mutations in dynein heavy chain in the mouse (Loa and Cra1) and in the dynactin subunit p150Glued in humans (G59S) lead to motor neuron degeneration and cell death. Loss of these motor neurons in turn leads to skeletal muscle weakness. One key role for dynein and dynactin in the neuron is retrograde axonal transport. Dynein is a non-redundant motor for this process, which is essential both for trophic factor signaling and for protein degradation. However, an additional cellular function of dynein and dynactin may be critical to the health and function of motor neurons. Studies in Drosophila have shown that dynactin is essential to maintain the integrity of neuromuscular junctions. Disruption of dynactin by either RNAi or expression of a mutant form of p150Glued leads to local disruption of the microtubule cytoskeleton in presynaptic motor neuron nerve terminals, followed by synapse retraction. However, the contribution of dynactin to synapse stability and function has not been examined in higher eukaryotes.
In collaboration with Dr. Erika Holzbaur and her lab, we are examining the effects of disruption of dynein or dynactin function on the stability and function of neuromuscular junctions. We are examining the effects of dynein/dynactin disruption in motor neurons on NMJ structure and function using zebrafish as a model system. We will express dynamitin, p150Glued, and p150Glued with the G59S mutation selectively in zebrafish motor neurons and assess NMJ structure and function. We anticipate that the motor neuron and neuromuscular defects in zebrafish will be similar to those observed in mice. We will thus attempt to validate the use of zebrafish as a tool to rapidly screen other mutations of interest. This information will then be used to focus efforts to generate additional mouse models of human motor neuron disease in future work.
Rotation Projects
The lab usually has one or more rotation students from the Neuroscience, CAMB, Biology and other graduate groups per semester. Prospective rotation students meet with Dr. Balice-Gordon to get an overview of current work, then meet with grad students and postdocs to learn more about projects of particular interest. Rotation students typically work closely with a lab member.
Spring, 2009
Emilia Moscato, NGG - Role of activity in shaping the functional properties of presynaptic terminals of hippocampal neurons in vitro.
Toni Moi-Prince, NGG - Effect of human auto-antibodies against NMDA and AMPA receptors on dendrite and spine stability.
Summer, 2009
Joseph Wasserman, NGG - Effect of human auto-antibodies against GluR1 / GluR2 subunits of AMPA receptors on GABAergic neurons in vitro, and effects of astrocytes on GABAergic neuron axon length and branching.
Fall, 2009
Ankit Jain , NGG - Relationship among serum and CSF antibody titers among patients with autoimmune encephalitis; development of rodent models of autoimmune encephalitis