Our long-term goal is to find out how axons and dendrites in the vertebrate brain determine when and where to form synapses. We focus on laminar specificity, a fundamental determinant of connectivity throughout the brain, whereby neuronal processes confine their arbors and synapses to specific laminae within a target area. Our object of study is the retinal ganglion cell (RGC), because it is relatively accessible, has a well-defined function, and displays exquisite laminar specificity: axons of distinct RGC subsets synapse in specific retinorecipient sublaminae of the superior colliculus, and their dendrites arborize in specific sublaminae of the inner plexiform layer (IPL), where they receive inputs from lamina-specified subsets of retinal interneurons. In work supported by this grant, we have obtained evidence that four related immunoglobulin superfamily (IgSF) adhesion molecules -Sidekick- 1, Sidekick-2, Dscam and DscamL- are critical determinants of an "IgSF code" that underlies some aspects of sublaminar specificity in the IPL. We will now use genetic methods to map the circuits that express these IgSF genes in mice, assess consequences of deleting them singly and in pairs, and determine whether they act cell-autonomously and/or homophilically. We will also test the possibility that close relatives of Sidekicks and Dscams, the Contactins, are additional components of the IgSF code. Then, we will use electrophysiological methods to relate circuit assembly to circuit function. We will map the receptive fields of IgSF-expressing RGC subsets, identify the interneurons that innervate then, and assess the effects of IgSF gene deletion on their properties. As an exacting test of our hypothesis, we will attempt to "rewire" a retinal circuit by replacing one IgSF gene with another, assessing the structural and functional effects of this "swap." Finally, we will extend our analysis to the laminar targeting of RGC axons in the superior colliculus. We recently generated a map of projections that RGC subsets form in collicular retinorecipient sublaminae, and will now classify the target cells on which axons of these subsets form synapses. With this foundation, we will test our hypothesis, based on results from chick optic tectum, that members of the cadherin superfamily (particularly Type II cadherins) are involved in the targeting of RGCs to sublaminae in the superior colliculus. Together these studies will contribute to elucidation of mechanisms that promote lamina-specific synapse formation and, by extension, synaptic specificity generally.

Public Health Relevance

During development, neurons connect with each other in very specific ways, forming the complex circuits that underlie our mental activities. Conversely, impaired development of these circuits is believed to underlie many behavioral disorders including autism and schizophrenia. Our long-term goal is to find some of the cells and molecules that determine when and where these connections, called synapses, form. To this end, we are focusing on the accessible visual system, in which we can assess the structural and functional consequences of controlled alterions in patterns of synaptic specificity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS029169-24
Application #
8585108
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
1991-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
24
Fiscal Year
2014
Total Cost
$535,944
Indirect Cost
$214,121
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Duan, Xin; Krishnaswamy, Arjun; De la Huerta, Irina et al. (2014) Type II cadherins guide assembly of a direction-selective retinal circuit. Cell 158:793-807
Hong, Y Kate; Park, SuHong; Litvina, Elizabeth Y et al. (2014) Refinement of the retinogeniculate synapse by bouton clustering. Neuron 84:332-9