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.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Steinmetz, Michael A
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Children's Hospital Boston
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