AMPA receptors (AMPAR) mediate the majority of fast excitatory synaptic transmission in the central nervous system. Trafficking of AMPARs in and out of synapses is a highly dynamic process and regulation of this trafficking plays a critical role in synaptic plasticity and learning and memory. However, the direct observation of dynamic AMPAR trafficking in live animals during synaptic plasticity has not been accomplished. To examine plasticity in vivo, we will investigate AMPAR dynamics in live animals undergoing various physiologically relevant sensory experiences using two-photon microscopy. We have been able to express pHluorin tagged AMPARs in layer ll/lll pyramidal neurons in the mouse barrel cortex using in utero electroporation. Following electroporation we make a cranial window over the barrel cortex region, map out barrel columns in the cortex using intrinsic optical imaging and then image pHluorin tagged AMPARs with two-photon microscopy. In preliminary studies we have investigated AMPAR dynamics under acute whisker deflection and chronic whisker trimming and regrowth conditions. We have found that both acute whisker deflection and whisker deprivation and regrowth lead to specific changes in AMPAR synaptic levels. To further understand how AMPARs behave during learning tasks, we will observe AMPAR dynamics in the mouse visual cortex during stimulus-specific response potentiation, a well-studied learning paradigm in the visual system and in other cortical regions. To study the molecular mechanisms underlying the induction and long-term maintenance of plasticity we will investigate the AMPAR subunit dependence and the structural regions of each subunit required for the regulation of AMPAR synaptic trafficking in vivo. In addition, we will examine AMPAR trafficking in vivo in our collection of transgenic and knock out mouse lines in which various key synaptic proteins, such as PSD95, SAP97, GRIP1/2, PICK1 and PKC zeta have been removed or altered. The findings from these experiments will help us identify the essential regulators of AMPAR trafficking in vivo under conditions that elicit synaptic plasticity and learning and elucidate the molecular mechanisms underlying synaptic plasticity in the brain in health and disease.

Public Health Relevance

This research will elucidate basic molecular mechanisms that regulate synaptic transmission and plasticity in the brain but it also has broad relevance for many neurological and psychiatric diseases. Dysfunction of synaptic transmission and plasticity underlies many neurological and psychiatric disorders. This research may therefore reveal novel targets for the development of therapeutic treatments for several brain disorders including schizophrenia autism depression drug addiction and pain

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Zhang-Hooks, YingXin; Agarwal, Amit; Mishina, Masayoshi et al. (2016) NMDA Receptors Enhance Spontaneous Activity and Promote Neuronal Survival in the Developing Cochlea. Neuron 89:337-50
Otsu, Yo; Couchman, Kiri; Lyons, Declan G et al. (2015) Calcium dynamics in astrocyte processes during neurovascular coupling. Nat Neurosci 18:210-8
Mariga, Abigail; Glaser, Juliane; Mathias, Leo et al. (2015) Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp. Cell Rep 13:1747-56
Wang, Han Chin; Lin, Chun-Chieh; Cheung, Rocky et al. (2015) Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells. Cell 163:1348-59
Zhang, Yong; Cudmore, Robert H; Lin, Da-Ting et al. (2015) Visualization of NMDA receptor-dependent AMPA receptor synaptic plasticity in vivo. Nat Neurosci 18:402-7
Nimmerjahn, Axel; Bergles, Dwight E (2015) Large-scale recording of astrocyte activity. Curr Opin Neurobiol 32:95-106
Rosa, Juliana M; Bos, Rémi; Sack, Georgeann S et al. (2015) Neuron-glia signaling in developing retina mediated by neurotransmitter spillover. Elife 4:
Rylkova, Daria; Crank, Aidan R; Linden, David J (2015) Chronic In Vivo Imaging of Ponto-Cerebellar Mossy Fibers Reveals Morphological Stability during Whisker Sensory Manipulation in the Adult Rat. eNeuro 2:
Placone, Amanda L; McGuiggan, Patricia M; Bergles, Dwight E et al. (2015) Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix. Biomaterials 42:134-43
Pelkey, Kenneth A; Barksdale, Elizabeth; Craig, Michael T et al. (2015) Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 85:1257-72

Showing the most recent 10 out of 13 publications