Synapse formation in the developing nervous system; in vivo imaging studies
Over the years, a major focus of our research has been to elucidate events that guide the development of synaptic connectivity in the living brain. The approach that we use is to image neurons in intact, non-mammalian vertebrate embryos as a means to provide new insight into the cellular, molecular, and activity-dependent processes that guide synaptogenesis in the central nervous system. Xenopus laevis tadpoles offer a uniquely accessible model system in which dynamic events can be studied because of the translucency of the embryos and because of their accessibility to experimental manipulation. The Xenopus visual system has provided us with a unique model system to study the molecular basis of developmental connectivity in vivo. In vivo time-lapse imaging studies from our laboratory first demonstrated that a process of iterative formation and elimination of synapses and neuronal branches guides synaptogenesis and is responsible for the selective stabilization of those synapses that are maintained during development. Our work with Xenopus allowed us to first demonstrate that the neurotrophin brain-derived neurotrophic factor (BDNF) -a potent modulator of multiple aspects of brain development- modulates synapse formation and stabilization by acting cell-autonomously in central neurons in vivo.
Studies from my laboratory have also focused on molecules and signaling pathways that interact with BDNF to control the development of retinotectal connectivity. For example, our studies established a role for MeCP2, the transcriptional modulator implicated in Rett syndrome. Moreover, in studies where we combined dietary manipulations in female Xenopus laevis frogs and in vivo imaging of developing tadpoles, we demonstrated that maternal n-3 polyunsaturated fatty acid (n-3 PUFA) deprivation impacts the morphological development of neurons by altering their dynamic branching and delaying maturation - through a mechanism that also involves BDNF. We have also shown that supplementation of maternal diets with DHA-rich fish oil can reverse deficits in morphology and connectivity of central neurons within the developing tadpole brain. Thus, the results of our studies emphasize the significant interactions between fatty acid metabolism and neurotrophic function, and further underscore the importance of proper maternal nutrition during gestational age for proper brain development and function among all vertebrate species.
In addition to the study of neurotrophic factors, my laboratory has also made substantial contributions to the understanding of the functions of classical axon guidance molecules, in particular netrin-1, during presynaptic retinal axon terminal and postsynaptic central neuron differentiation in the vertebrate visual system. Our most recent studies focused on the differential cellular and molecular mechanisms by which Down syndrome cell adhesion molecule (DSCAM) impacts retinotectal circuit formation and maintenance in the intact Xenopus brain, and how these changes can inform us about cellular mechanisms by which DSCAM affects the human brain. DSCAM is one of the key molecules whose dysregulation has been associated to both autism and Down Syndrome, but whether it acts independently to modulate neural circuit wiring in vertebrates remained to be understood. Our laboratory recently demonstrated multiple, novel cell-autonomous functions of DSCAM during visual system wiring, where DSCAM limits dendritic differentiation of postsynaptic brain neurons while independently facilitates retinal axon arbor growth at the postsynaptic target.
Thus, by using our accessible animal model system where the interplay between pre- and postsynaptic contributions to circuit formation can easily be teased apart, we have aimed to provide valuable insights into fundamental mechanisms of central nervous system development and to advance the understanding of development deficiencies that can affect brain function. Current studies are focused on the interactions between endocannabinoid signaling, neurotrophic factors, and cell-adhesion molecules during the development of synaptic connectivity in the intact brain.
Santos RA, Fuertes AJC, Short G, Donohue KC, Shao H, Quintanilla J, Malakzadeh P, Cohen-Cory S. DSCAM differentially modulates pre- and postsynaptic structural and functional central connectivity during visual system wiring. Neural Development 13:22, 2018. doi:10.1186/s13064-018-0118-5
A.N. Nagel, S. Marshak, C. Manitt, R.A. Santos, M.A. Piercy, S.D. Mortero, N.J. Shirkey-Son, and S. Cohen-Cory. Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo. Neural Development 10:14, 2015. doi:10.1186/s13064-015-0041-y
M. Igarashi, R.A. Santos, S. Cohen-Cory. Impact of Maternal n-3 Polyunsaturated Fatty Acid Deficiency on Dendritic Arbor Morphology and Connectivity of Developing Xenopus laevis Central Neurons In Vivo. Journal of Neuroscience, 35; 6079-6092, 2015.
S. Marshak, M.M. Meynard, Y.A. De Vries, A. Kidane and S. Cohen-Cory. Cell-autonomous Alterations in Dendritic Morphology and Connectivity Induced by Overexpression of MeCP2 in Xenopus Central Neurons in vivo. PLos One, 7, issue 3, e33153, March 2012.
N. Shirkey, C. Manitt, L. Zuniga and S. Cohen-Cory. Dynamic responses of Xenopus retinal ganglion cell axon growth cones to netrin-1 as they innervate their in vivo target. Developmental Neurobiology, 72; 628–648, 2012.
S. Cohen-Cory, A. Kidane, N. Shirkey and S. Marshak. Brain-Derived Neurotrophic Factor and the Development of Structural Neuronal Connectivity. Developmental Neurobiology, 70; 271-288, 2010.
A.M. Nikolakopoulou, M. M. Meynard, S. Marshak and S. Cohen-Cory. Synaptic Maturation of the Xenopus Retinotectal System: Effects of Brain-derived Neurotrophic Factor on Synapse Ultrastructure. Journal of Comparative Neurology, 518; 972-989, 2010.
C. Manitt, A.M. Nikolakopoulou, D. Almario, S. Nguyen, and S. Cohen-Cory. Netrin Participates in the Development of Retinotectal Synaptic Connectivity by Modulating Axon Arborization and Synapse Formation in the Developing Brain. Journal of Neuroscience, 29; 11065-11077, 2009.
S. Marshak, A.M. Nikolakopoulou, R. Dirks, G.J.M. Martens and S. Cohen-Cory. Cell autonomous TrkB signaling in presynaptic retinal ganglion cells mediates axon arbor growth and synapse maturation during the establishment of retinotectal synaptic connectivity. Journal of Neuroscience, 27, 2444-2456, 2007.
A.L. Sanchez, B.J. Matthews, M.M. Meynard, B. Hu, S. Javed and S. Cohen-Cory. BDNF increases synapse density in dendrites of developing tectal neurons in vivo. Development, 133, 2477-2486, 2006.
B. Hu, A. M Nikolakopoulou and S. Cohen-Cory. BDNF stabilizes synapses and maintains the structural complexity of optic axons in vivo. Development, 132, 4285-4298, 2005.
S. Cohen-Cory and B. Lom. Neurotrophic Regulation of Retinal Ganglion Cell Synaptic Connectivity: From Axons and Dendrites to Synapses. International Journal of Developmental Biology, 48; 947-956, 2004.
N. Prakash, S. Cohen-Cory, S. Penshuk, R. Frostig. The basal forebrain cholinergic system is involved in rapid nerve growth factor (NGF)-induced plasticity in the barrel cortex of adult rats. Journal of Neurophysiology, 91; 424-37, 2004.
T.S.Tran, S. Cohen-Cory, and P.E. Phelps. Embryonic GABAergic Spinal Commissural Neurons Project Rostrally To Mesencephalic Targets. Journal of Comparative Neurology, 475; 327-339, 2004.
S. Cohen-Cory. The developing synapse: construction and modulation of synaptic structure and circuits. Science 298; 770-776, 2002.
B. Lom, J. Cogen, A. Lontok Sanchez, T. Vu, and S. Cohen-Cory. Local and target-derived BDNF exert opposing effects on the dendritic arborization of retinal ganglion cells in vivo. Journal of Neuroscience 22; 7639-49, 2002.
B. Alsina, T. Vu and S. Cohen-Cory. Visualizing Synapse Formation in Arborizing Optic Axons in vivo: Dynamics and Modulation by BDNF. Nature Neuroscience, 4; 1093-101, 2001.
J. Cogen and S. Cohen-Cory. Nitric oxide modulates retinal ganglion cell axon arbor remodeling in vivo. Journal of Neurobiology 45; 120-133, 2000.
N. Prakash, P. Vanderhaeghen, S. Cohen-Cory, J. Frisén, J. G. Flanagan, and R. D. Frostig. Malformation of the functional cortical somatosensory map in adult ephrin-A5 knockout mice revealed by in vivo functional imaging. Journal of Neuroscience 20; 5841-5847, 2000.
B. Lom and S. Cohen-Cory. BDNF differentially regulates retinal ganglion cell dendritic and axonal arborization in vivo. Journal of Neuroscience, 19; 9928-9938, 1999.
S. Cohen-Cory. BDNF modulates, but does not mediate, activity-dependent branching and remodeling of optic axon arbors in vivo. Journal of Neuroscience 19; 9996-10003, 1999.
S. Cohen-Cory, E. Escandón and S.E. Fraser. The cellular patterns of BDNF and trkB expression suggest multiple roles for BDNF during Xenopus visual system development. Developmental Biology, 179, 102-115 1996.
N. Prakash, S. Cohen-Cory and R.D. Frostig. Rapid and opposite effects of BDNF and NGF on the functional organization of the adult cortex in vivo. Nature 381, 702-706, 1996.
S. Cohen-Cory and S.E. Fraser. Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature 378, 192-196, 1995.
S. Cohen-Cory and S.E. Fraser. BDNF in the development of the visual system of Xenopus. Neuron 12; 747-761, 1994.
S. Cohen-Cory, R. C. Elliott, C.F. Dreyfus and I.B. Black. Depolarizing influences increase low-affinity NGF receptor gene expression in cultured Purkinje neurons. Experimental Neurology, 119; 165-175, 1993.
S. Cohen-Cory, C.F. Dreyfus and I.B. Black. NGF and excitatory neurotransmitters regulate survival and morphogenesis of cultured cerebellar Purkinje cells. Journal of Neuroscience, 11; 462-471, 1991.
S. Cohen-Cory, C.F. Dreyfus and I.B. Black. Expression of high- and low-affinity nerve growth factor receptors by Purkinje cells in the developing rat cerebellum. Experimental Neurology, 105: 104-109, 1989.
Society for Neuroscience
Neurobiology and Behavior
Interdepartmental Neuroscience Program
Center for the Neurobiology of Lerning and Memory
Center for Autism Research and Treatment