The mechanisms underlying the formation and refinement of synaptic circuits during development are a subject of intense investigation. At many synapses in the central nervous system, initial connections are excessive and redundant. However, these connections are refined in the course of development, as unnecessary connections are eliminated and proper ones are strengthened. We have characterized changes in synaptic function in a powerful model for synapse development, the connection between retinal ganglion cells and thalamic relay neurons of the lateral geniculate nucleus in the thalamus. Using electrophysiological techniques and a mouse brain slice preparation, we have uncovered a previously unrecognized phase of experience- dependent synapse remodeling at the retinogeniculate synapse. At a time after the bulk of synapse elimination and synaptic strengthening has occurred, we find that deprivation by dark rearing results reorganization of the circuit, as connections between retina and thalamus become weaker and more abundant. This late period of remodeling is activated by visual experience during the week after eye-opening. Our findings suggest that there is a period in late development when synapses in the thalamus are unexpectedly malleable, and that pairings between RGC and thalamic relay neurons can be rewired. Here we propose to define the mechanisms that govern this period of plasticity. First, we will determine the structural basis for the changes in connectivity that we observe during the sensory-dependent period in the LGN. Second, we will identify and characterize molecular mechanisms that underlie vision-dependent plasticity in the thalamus. Finally, we will examine the influence of the cortex on retinogeniculate development. The results from these studies will lay the groundwork for our understanding of a late developmental period during which excitatory synaptic circuits in the thalamus are shaped by the external environment. The revelation that connections in the thalamus can remodel in an experience-dependent manner has important implications for our understanding of the mature and developing brain. Because sensory information is relayed to the cortex via the thalamus, disruption in thalamic circuitry can result in aberrant information processing and cortical function. Thus elucidation of the mechanisms driving thalamic plasticity will be highly relevant for our understanding of neurodevelopmental disorders including mental retardation, autism, epilepsy and cognitive diseases.

Public Health Relevance

We have previously discovered a period during late development when synaptic circuits in the thalamus, a subcortical region in the brain that processes incoming information and relays this information to the cortex, can be remodeled by experience. In this grant we propose to identify the mechanisms that are important in triggering, maintaining and ending this period of robust synaptic plasticity. Understanding these basic processes may help guide the design of future therapies for neurological disorders due to abnormal synaptic connections such as some forms of epilepsy, cognitive disorders and mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013613-06A1
Application #
7888888
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Steinmetz, Michael A
Project Start
2001-07-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
6
Fiscal Year
2010
Total Cost
$509,629
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Liang, Liang; Fratzl, Alex; Goldey, Glenn et al. (2018) A Fine-Scale Functional Logic to Convergence from Retina to Thalamus. Cell 173:1343-1355.e24
Hong, Y Kate; Burr, Eliza F; Sanes, Joshua R et al. (2018) Heterogeneity of retinogeniculate axon arbors. Eur J Neurosci :
Thompson, Andrew; Gribizis, Alexandra; Chen, Chinfei et al. (2017) Activity-dependent development of visual receptive fields. Curr Opin Neurobiol 42:136-143
Thompson, Andrew D; Chen, Chinfei (2017) The importance of constructive feedback: Implications of top-down regulation in the development of neural circuits. Neurogenesis (Austin) 4:e1287553
Litvina, Elizabeth Y; Chen, Chinfei (2017) An evolving view of retinogeniculate transmission. Vis Neurosci 34:E013
Litvina, Elizabeth Y; Chen, Chinfei (2017) Functional Convergence at the Retinogeniculate Synapse. Neuron 96:330-338.e5
Chen, Chinfei; Bickford, Martha E; Hirsch, Judith A (2016) Untangling the Web between Eye and Brain. Cell 165:20-21
Bei, Fengfeng; Lee, Henry Hing Cheong; Liu, Xuefeng et al. (2016) Restoration of Visual Function by Enhancing Conduction in Regenerated Axons. Cell 164:219-232
Thompson, Andrew D; Picard, Nathalie; Min, Lia et al. (2016) Cortical Feedback Regulates Feedforward Retinogeniculate Refinement. Neuron 91:1021-1033

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