2014 research

My laboratory is interested in understanding mechanisms of neuronal connectivity and plasticity, how these processes are modulated by environmental and genetic factors, and how they are altered in human diseases and under drug conditions.  We will continue to employ a combination of behavioral, physiological, pharmacological, and genomic approaches for the following projects.

1. Dendritic mechanisms underlying learning and plasticity.  Dendrites are highly branched structure and provide the substrate for receiving and integrating incoming synaptic information at the level of individual neurons.  In the past, my research has been focused on how ion channels in dendrites control the membrane excitability, shape the kinetics of synaptic responses, and regulate neural plasticity.  In addition to ion channels and receptors, dendrites are also home to a host of RNA species including non-coding RNAs (ncRNAs).  However, thus far, only a small handful has been closely examined in the CNS. A large pool of ncRNAs critical for CNS function is yet to be discovered and characterized.  We are conducting a large-scale screening and functional characterization of dendritic ncRNAs involved in learning and memory in the hippocampal system.  We expect that this large scale screening and functional analysis will lead to a leap forward in resolving the roles played by ncRNAs in major CNS functions.  This approach, once established, will be further applied to neurodegenerative disorders, especially these characteristic with learning and memory deficits such as Alzheimer’s Disease (AD). 

2. Mapping synaptic connectivity and activity in the medial prefrontal cortex. The prefrontal cortex (PFC) has been viewed as a central site for information processing.  However, lack of access to various afferent fibers in vitro hampers studies on how synaptic inputs are integrated and drive neuronal activity of PFC.  To this end, we have developed a slice preparation where we are able to identify and selectively activate the hippocampal projection to the medial PFC. We expect to extend our studies to include other afferent pathways by employing “optogenetic” approaches.  In addition to afferent inputs, intrinsic connectivity serves as another important means to sustain network activity.  Decreased network activity and NMDA receptor dysfunction are implicated in the pathophysiology of many disorders linked to PFC such as schizophrenia and post-traumatic stress disorder. Consequently, co-agonist regulation of NMDAR is currently a target for clinical trials treating these disorders.  Mapping both connectivity and activity in PFC is expected to provide key information on PFC function.

3. Discovering fast-acting antidepressants.  The prefrontal cortex (PFC) is a primary target of stress.  Accumulating evidence suggests a link between chronic stress and hypoglutamatergic transmission in PFC, especially these mediated by NMDA receptors, raising the possibility that NMDAR represents a therapeutic target for chronic stress-induced cognitive deficits.  Indeed, the field of antidepressant research has recently been reinvigorated by the discovery that low dose ketamine has a fast-actin and long lasting antidepressant effect in humans and in rodents.  The downside of ketamine treatment is its abuse potential and the dissociative and psychotomimetic side effects.  We are currently testing candidate drugs targeting NMDA receptors with the goal of discovering fast-acting and long-lasting antidepressants.

Publications

Pisansky MT, Wickham RJ, Su J, Fretham S, Yuan LL, Sun M, Gewirtz JC, Georgieff MK. Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex. Hippocampus. doi: 10.1002/hipo.22151., 2013

Lockridge A, Newland B, Printen S, Romero GE, Yuan LL. Head movement: a novel serotonin-sensitive behavioral endpoint for tail suspension test analysis. Behav Brain Res 246:168-178., 2013

Lockridge A, Romero G, Harrington J, Newland B, Gong Z, Cameron A, Yuan LL . Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine. Alcohol 46:389-400., 2012

Meehan AL, Yang X, Yuan LL, Rothman SM. Levetiracetam has an activity-dependent effect on inhibitory transmission. Epilepsia 53:469-476., 2012

Parent M, Yuan LL. Automated detection and analysis of neuronal persistent activity. J Neurosci Methods 201:361-367., 2011

Meehan AL, Yang X, McAdams BD, Yuan L, Rothman SM. A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106:1227-1239., 2011

Lockridge A, Yuan LL. Spatial learning deficits in mice lacking A-type K(+) channel subunits. Hippocampus 21:1152-1156., 2011

Zhao C, Wang L, Netoff T, Yuan LL. Dendritic mechanisms controlling the threshold and timing requirement of synaptic plasticity. Hippocampus 21:288-297., 2011

Kong F, J Zhu, J Wu, J Peng, Y Wang, Q Wang, S Fu, LL Yuan, T Li. dbCRID: A Database of Chromosomal Rearrangements in Human Diseases. Nucleic Acids Res 39: D895-900, 2011

Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067-1081., 2010

Lockridge A, Su J, Yuan LL. Abnormal 5-HT modulation of stress behaviors in the Kv4.2 knockout mouse. Neuroscience 170:1086-1097., 2010

Parent MA, Wang L, Su J, Netoff T, Yuan LL. Identification of the hippocampal input to medial prefrontal cortex in vitro. Cereb Cortex 20:393-403., 2010

Wang L, Yuan LL. Activation of M2 muscarinic receptors leads to sustained suppression of hippocampal transmission in the medial prefrontal cortex. J Physiol 587:5139-5147., 2009

Chen X*, LL Yuan*, C Zhao, S Birnbaum, A Frick, WE Jung, TL Schwarz, JD Sweatt, D Johnston. ( * Co-first authors) Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction of long-term potentiation in hippocampal CA1 pyramidal neurons. J. Neurosci. 26: 12143-12151. , 2006

Lauver A, LL Yuan, A Jeromin, BM Nadin, J Rodriguez-Arellano, H Davies, M Steward, G-Y Wu, P Pfaffinger. Manipulating Kv4.2 expression identifies a specific component of hippocampal pyramidal neuron A current that depends upon Kv4.2 expression. J. Neurochem. 99: 1207-1223., 2006

Yuan LL, X Chen. Diversity of potassium channels in neuronal dendrites. Prog. Neurobiol. 8: 374-89., 2006

Yuan LL, X Chen, K Kunjil, P Pfaffinger, and D Johnston. Increase in the rate of inactivation of expressed and native A-type K+ channels by a MEK inhibitor. Am. J. Physiol. (Cell Physiol.) 290:C165-71., 2006

Varga AW*, LL Yuan*, AE Anderson, L Schrader, G-Y Wu, D. Johnston, JD Sweatt. (* Co-first authors) CaMKII modulates Kv4.2 channel expression and upregulates neuronal A-type potassium current. J. Neurosci. 24: 3643-3654. , 2004

Birnbaum S, A Varga, LL Yuan, A Anderson, D Sweatt, L Schrader. Functions and regulation of Kv4-family A-type potassium channels. Physiol. Rev. 84: 803-833., 2004

Johnston D, BR Christie, A Frick, R Gray, DA Hoffman, JC Magee, LK. Schexnayder, S Watanabe, LL Yuan. Active dendrites, K+ channels, and synaptic plasticity. Phil. Trans. R. Soc. Lond. B 358: 667-674, 2003

Jeromin A, LL Yuan, A Frick, P Pfaffinger, and D Johnston (2003). A modified Sindbis virus for long-term gene expression in neurons. J. Neurophys. 90:2741-2745, 2003

Liang Y, LL Yuan, R Gray and D Johnston. Calcium signaling at single mossy fiber presynaptic terminals in the rat hippocampus. J. Neurophys. 87: 1132-1137., 2002

Yuan LL, JP Adams, M Swank, JD Sweatt and D Johnston. Protein kinase modulation of dendritic transient K+ channels in hippocampus involves a MAPK pathway. J. Neurosci. 22: 4860-4868., 2002

Yuan LL and BS Ganetzky. Searching for molecules mediating glial-neuronal communication. Molecular Psychiatry 4: 408-409., 1999

Yuan LL and BS Ganetzky. A glial-neuronal signaling pathway revealed by mutations in a Neurexin-related protein. Science 283: 1343-1345., 1999

Yuan LL and XL Yang. Selective suppression of rod signal transmission by cobalt ions of low levels in carp retina. Science in China, Ser. C 402: 128-136. , 1997

Awards and honors

2009-2011 - Whitehall Foundation Grant Award

2008-2009 - Minnesota Medical Foundation

2005-2010 - NIH Research Project Grant

2005-2006 - NIH Small Grant Program

2002 - Chunhui Project, Ministry of Education (MOE), China

1998 - Jerzy Rose Award, University of Wisconsin, Madison