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 #
5R01EY013613-09
Application #
8450220
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
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$493,636
Indirect Cost
$209,937
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Louros, Susana R; Hooks, Bryan M; Litvina, Liza et al. (2014) A role for stargazin in experience-dependent plasticity. Cell Rep 7:1614-25
Hong, Y Kate; Park, SuHong; Litvina, Elizabeth Y et al. (2014) Refinement of the retinogeniculate synapse by bouton clustering. Neuron 84:332-9
Hauser, Jessica L; Liu, Xiaojin; Litvina, Elizabeth Y et al. (2014) Prolonged synaptic currents increase relay neuron firing at the developing retinogeniculate synapse. J Neurophysiol 112:1714-28
Lin, David J; Kang, Erin; Chen, Chinfei (2014) Changes in input strength and number are driven by distinct mechanisms at the retinogeniculate synapse. J Neurophysiol 112:942-50
Hauser, Jessica L; Edson, Eleanore B; Hooks, Bryan M et al. (2013) Metabotropic glutamate receptors and glutamate transporters shape transmission at the developing retinogeniculate synapse. J Neurophysiol 109:113-23
Hong, Y Kate; Chen, Chinfei (2011) Wiring and rewiring of the retinogeniculate synapse. Curr Opin Neurobiol 21:228-37
Hooks, Bryan M; Chen, Chinfei (2008) Vision triggers an experience-dependent sensitive period at the retinogeniculate synapse. J Neurosci 28:4807-17
Liu, Xiaojin; Chen, Chinfei (2008) Different roles for AMPA and NMDA receptors in transmission at the immature retinogeniculate synapse. J Neurophysiol 99:629-43
Hooks, Bryan M; Chen, Chinfei (2007) Critical periods in the visual system: changing views for a model of experience-dependent plasticity. Neuron 56:312-26
Hooks, Bryan M; Chen, Chinfei (2006) Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52:281-91

Showing the most recent 10 out of 11 publications