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.
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.
|Hou, Guoqiang; Smith, Alison G; Zhang, Zhong-Wei (2016) Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse. J Neurosci 36:7246-52|
|Zhang, Wen; Zhang, Lifeng; Liang, Bo et al. (2016) Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat Neurosci 19:557-9|
|Zhang, Wen; Peterson, Matthew; Beyer, Barbara et al. (2014) Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures. J Neurosci 34:2754-63|
|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|