How ascending sensory information is integrated in the neocortex has been extensively studied in the last several decades. This sustained interest in cortical sensory integration stems from the belief that sensory processing underlies key aspects of cognitive functions and dysfunctions, such as sensory perception, sensory discrimination, trauma and other cognitive dysfunctions. In sensory cortices, layer 4 constitutes the main target layer for specific thalamocortical afferents and is the layer in which cortical sensory processing begins. It is known that only approximately 5-15% of excitatory synapses onto layer 4 neurons are from thalamocortical (TC) fibers, whereas the majority of other excitatory synapses are from intracortical (IC) fibers. However, the relative importance of TC and IC connections to sensory processing is still in debate, due in part to the poor understanding of the cellular and molecular properties of these connections. Some studies have suggested that TC synapses are strong and reliable enough to convey sensory information into the cortex, while others have argued that recurrent IC synapses are indispensable in amplifying and dynamically regulating TC inputs, hi addition, how synaptic strengths of TC and IC connections are maintained and regulated is unclear. Combining electrophysiology, molecular biology and genetics techniques, we have recently found that synaptic responses at IC and TC synapses display different kinetics, which may represent a novel and important strategy for integrating and amplifying sensory inputs. Our preliminary data also suggest that the differences of kinetics at these synapses are due to synapse-specific delivery of distinct AMPA-sensitive glutamate receptors (-Rs). Based on these results, I hypothesize that postsynaptic regulation of transmission is synapse-specific in layer 4 cortical neurons. We will examine what controls the synaptic kinetics and efficacy of transmission at IC synapses. Moreover, we will determine what regulates synaptic kinetics and efficacy of transmission at TC synapses. Finally, we will investigate how IC and TC synapses maintain synaptic strength. Because different AMPA-Rs exhibit distinct properties in mediating synaptic transmission and in controlling synaptic efficacy, the results from this project should aid the understanding of sensory physiology of neocortex and cortical pathologies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Wang, Guangfu; Bochorishvili, Genrieta; Chen, Yucai et al. (2015) CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy. Genes Dev 29:1535-51
Wang, Guangfu; Wyskiel, Daniel R; Yang, Weiguo et al. (2015) An optogenetics- and imaging-assisted simultaneous multiple patch-clamp recording system for decoding complex neural circuits. Nat Protoc 10:397-412
Jiang, Xiaolong; Wang, Guangfu; Lee, Alice J et al. (2013) The organization of two new cortical interneuronal circuits. Nat Neurosci 16:210-8
Stornetta, Ruth L; Zhu, J Julius (2011) Ras and Rap signaling in synaptic plasticity and mental disorders. Neuroscientist 17:54-78
Kielland, Anders; Bochorishvili, Genrieta; Corson, James et al. (2009) Activity patterns govern synapse-specific AMPA receptor trafficking between deliverable and synaptic pools. Neuron 62:84-101
Zhu, J Julius (2009) Activity level-dependent synapse-specific AMPA receptor trafficking regulates transmission kinetics. J Neurosci 29:6320-35
Hu, Hailan; Qin, Yi; Bochorishvili, Genrieta et al. (2008) Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J Neurosci 28:7847-62
Ouyang, Ming; Zhang, Lei; Zhu, J Julius et al. (2008) Epac signaling is required for hippocampus-dependent memory retrieval. Proc Natl Acad Sci U S A 105:11993-7
Lai, Chen; Xie, Chengsong; McCormack, Stefanie G et al. (2006) Amyotrophic lateral sclerosis 2-deficiency leads to neuronal degeneration in amyotrophic lateral sclerosis through altered AMPA receptor trafficking. J Neurosci 26:11798-806