The refinement of neuronal connections, which consists of selective elimination and consolidation of synapses, is a key mechanism of neuroplasticity. Disruptions of this process, caused by either environmental or genetic factors or both, are thought to be a substrate for altered information processing and abnormal behaviors associated with common developmental brain disorders including autism and schizophrenia. Mechanisms underlying synaptic refinement during development may also be involved in plasticity in the adult brain associated with learning, memory, and neuronal injuries. The long-term goal of this research is to understand how neurons in immature brains selectively eliminate some synapses while reinforcing others. We use sensory relay synapses in the thalamus of the mouse as a model to investigate the cellular and molecular mechanisms underlying synaptic refinement. We will use a novel slice preparation to quantitatively analyze the number and properties of synapses at the single-cell level in whisker sensory relay neurons in the thalamus of normal and genetically modified mice. We will determine the structural basis of synaptic refinement through quantitative analyses of the synapse using light and electron microscopy.
Specific Aim 1 proposes to analyze the effects of sensory deprivation and identify the underlying cellular and molecular mechanisms. We hypothesize that sensory experience plays a critical role in developmental refinement of the synapse.
Specific Aim 2 proposes to investigate the roles of NMDA (N-methyl-D-aspartate) receptor subunits NR2A and NR2C at this synapse. We hypothesize that the developmental switch of NMDA receptor composition plays an important role in synaptic refinement.

Public Health Relevance

This research will advance our understanding of autism, epilepsy, mood and anxiety disorders, and schizophrenia, and may provide opportunity for the development of new and improved treatments for neural injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064013-03
Application #
8063475
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Talley, Edmund M
Project Start
2009-08-01
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2011
Total Cost
$373,013
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Zhang, Zhong-wei; Peterson, Matthew; Liu, Hong (2013) Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses. Proc Natl Acad Sci U S A 110:1095-100
Wang, Hao; Liu, Hong; Storm, Daniel R et al. (2011) Adenylate cyclase 1 promotes strengthening and experience-dependent plasticity of whisker relay synapses in the thalamus. J Physiol 589:5649-62
Wang, Hao; Liu, Hong; Zhang, Zhong-wei (2011) Elimination of redundant synaptic inputs in the absence of synaptic strengthening. J Neurosci 31:16675-84