Perelman School of Medicine at the University of Pennsylvania

Department of Neuroscience

Marc V Fuccillo, M.D., Ph.D.

faculty photo
Assistant Professor of Neuroscience
Department: Neuroscience
Graduate Group Affiliations

Contact information
University of Pennsylvania, Department of Neuroscience
415 Curie Boulevard
Clinical Research Building, Room 226
Philadelphia, PA 19104
Office: (646) 483-6714
Lab: (215) 898-8744
Education:
B.A. (Molecular and Cellular Biology, Music Performance (Violin))
Brown University, 1998.
Ph.D. (Developmental Genetics)
New York University School of Medicine, 2007.
M.D.
New York University School of Medicine, 2008.
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Description of Research Expertise

Research Interests: The synaptic and circuit mechanisms of behavioral control

Keywords: Synaptic transmission, striatal circuits, inhibition, mouse genetics, in vitro electrophysiology, goal-directed behavior, motor control, neuropsychiatric disease modeling

Research Details: My laboratory is interested in understanding how neural circuits projecting to the striatum regulate mouse behavior – from simple motor patterns to complex goal-directed actions. To do this, we explore striatal circuits at the molecular, synaptic and behavioral level. We employ a range of technologies in seeking a more comprehensive understanding of the normal regulation of striatal function as well as its disruption in mouse models of neuropsychiatric disease.

During my postdoctoral training I initiated a project investigating the circuit and synaptic basis of autism-associated abnormalities in behavioral control. We focused on the enhanced motor learning of mice with mutations in Neuroligin3 (NL3), an autism-associated synaptic adhesion molecule thought to guide synapse assembly. We postulated that their improved performance on the accelerating rotarod - a phenotype displayed by many autism-relevant mouse mutants – might serve as a behavioral endophenotype for the repetitive motor routines commonly seen in autism spectrum disorders. Quantitative video-capture analyses of rotarod learning demonstrated that improved performance in mutant mice was associated with accelerated formation of stereotyped patterns of paw placement. Through targeted viral injections and genetic cell-type specific manipulation of NL3 function, we found that deletion of NL3 in D1 dopamine receptor positive medium spiny neurons (D1R+ MSNs) of the nucleus accumbens (ventral striatum) was sufficient to generate enhanced rotarod learning and other stereotyped behaviors. Subsequent analysis of synaptic transmission identified a cell-type specific deficit in inhibitory transmission onto D1R+ MSNs, which lead to an excitatory-inhibitory imbalance that likely enhanced formation of motor patterns in NL3 autism models. Current studies are using similar molecular/genetic techniques to explore the circuit basis of reward-related abnormalities seen in operant behaviors with NL3 mutant mice.

Neuroligins and their presynaptic Neurexin ligands are part of an intricate array of synaptic adhesion molecules (SAMs) that bestow circuit specific characteristics to synaptic connections. Understanding the diversity of SAM expression could provide an understanding of how synapse specificity is cooperatively determined, as well as reveal circuits that lack molecular redundancy and are thereby more vulnerable to individual genetics insults. To explore this concept, I investigated SAM diversity within striatal and hippocampal circuits through a single-cell transcriptional analysis. Using microfluidics-based quantitative-PCR technology combined with single cell isolation of neurons defined by transgenic reporter mice and viral synaptic tracing, I have begun to characterize circuit-specific expression of synaptic adhesion molecules as well as other gene families that may underlie diversity in synaptic connectivity, regulation and function.


Going forward, my lab will use complementary approaches to explore how neural circuits projecting to the striatum function in regulating behavior.

I. Is there a molecular logic to the composition of striatal circuits?
The striatum integrates neuronal connections from prefrontal and motor cortices, amygdala, hippocampus, thalamus, as well as dopaminergic and serotonergic neuromodulatory systems. Do these circuits possess unique molecular architectures that bestow specific synaptic connectivity, modulation and behavioral function?

II. How do striatal circuits shape behavioral control?
The striatum is considered a central node in action selection as it links neural circuitry that analyzes decision-relevant information to neuronal populations responsible for the execution of discrete behavioral responses. How do striatal circuits and their synapses support aspects of action selection and how does dysfunction within these circuits manifest behaviorally?

III. What can mouse models of autism, schizophrenia and OCD tell us about the role of striatal circuitry in disease pathophysiology?
Genetic mouse models of neuropsychiatric disease provide a unique opportunity to understand how genetic insults translate into behavioral abnormalities. Can striatal circuit and synaptic dysfunction explain deficits in behavioral control observed in mouse models of these diseases? Do common physiological abnormalities exist across disease models? How do environmental factors and genetic modifiers modulate disease-relevant striatal circuitry?

Rotation Projects:
Please contact Dr. Fuccillo regarding potential rotation projects.

Lab Personel:
Marc Fuccillo, MD/PhD, PI, fuccillo@mail.med.upenn.edu

Selected Publications

Rothwell P.E*., Fuccillo M*, Maxeiner S., Hayton S.J., Lim B.K., Fowler S.C., Malenka R.C., Südhof T.C (*equal contribution): Autism-Associated Neuroligin-3 Mutations Disrupt Striatal Circuits Underlying Repetitive Motor Routines. Cell 158(1): 198-212, July 2014.

Soler-Llavina G.J.*, Fuccillo M.*, Ko J., Südhof T.C., Malenka R.C. (*equal contribution): The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo. Proceedings of the National Academy of Sciences 108(40): 16502-16509, 2011.

Ko J., Soler-Llavina G.J., Fuccillo M., Malenka R.C., Südhof T.C.: Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons. The Journal of Cell Biology 194(2): 323-334, 2011.

Zhang C., Atasoy D., Araç D., Yang X., Fuccillo M., Robison A.J., Ko J., Brunger A.T., Südhof T.C.: Neurexins physically and functionally interact with GABA(A) receptors. Neuron 66(3): 403-416, 2010.

Ko J., Fuccillo M., Malenka R.C., Südhof T.C.: LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron 64(6): 791-798, 2009.

Butt, S.J.B.*, Sousa V.*, Fuccillo, M., Hjerling-Leffler, J., Miyoshi, G., Kimura, S., Fishell, G. (*equal contribution): The requirement of Nkx2.1 in the temporal specification of cortical interneuron subtypes. Neuron 59(5): 722-732, 2008.

Fuccillo, M., Joyner A.L., and Fishell G.: Morphogen to mitogen: the multiple roles of hedgehog signaling in vertebrate neural development. Nature Reviews Neuroscience 7(10): 772-783, 2006.

Fuccillo, M., Rutlin, M., Fishell, G.: Removal of Pax6 partially rescues the loss of ventral structures in Shh null mice. Cerebral Cortex Supp1: 96-102, 2006.

Butt, S. J. B.*, Fuccillo, M.*, Nery, S., Noctor, S., Kriegstein, A., Corbin, J.G., Fishell G. (*equal contribution): The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48(4): 591-604, 2005.

Fuccillo, M., Rallu, M., McMahon A.P., and Fishell G.: Temporal Requirement for Hedgehog Signaling in Ventral Telencephalic Patterning. Development 131(20): 5031-5040, 2004.

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Last updated: 09/28/2017
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