Bio


neuroscientist, former rower/current runner, lover of live music

Academic Appointments


  • Basic Life Science Research Associate, Biology

Honors & Awards


  • NIH NRSA for Individual Postdoctoral Fellows (F32), National Institute of Mental Health (NIMH) (2011-2014)
  • Graduate Research Fellowship, National Science Foundation (2007-2010)
  • Best Teaching Assistant, Biology Dept., University of California, San Diego (2007, 2008)
  • Best Student Research Presentation, Annual Departmental Retreat, University of California, San Diego (2007)
  • Cell and Molecular Genetics Training Grant, University of California, San Diego (2006-2007)

Professional Education


  • Bachelor of Science, University of Washington, Biology (2003)

Current Research and Scholarly Interests


I'm interested in uncovering how norepinephrine circuits in the brain modulate diverse behaviors in the mouse.

All Publications


  • Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron Huang, W., Guenthner, C. J., Xu, J., Nguyen, T., Schwarz, L. A., Wilkinson, A. W., Gozani, O., Chang, H. Y., Shamloo, M., Luo, L. 2016; 92 (2): 392-406

    Abstract

    Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), which is associated with diverse neurodevelopmental and behavioral symptoms as well as obesity. RAI1 encodes a nuclear protein but little is known about its molecular function or the cell types responsible for SMS symptoms. Using genetically engineered mice, we found that Rai1 preferentially occupies DNA regions near active promoters and promotes the expression of a group of genes involved in circuit assembly and neuronal communication. Behavioral analyses demonstrated that pan-neural loss of Rai1 causes deficits in motor function, learning, and food intake. These SMS-like phenotypes are produced by loss of Rai1 function in distinct neuronal types: Rai1 loss in inhibitory neurons or subcortical glutamatergic neurons causes learning deficits, while Rai1 loss in Sim1(+) or SF1(+) cells causes obesity. By integrating molecular and organismal analyses, our study suggests potential therapeutic avenues for a complex neurodevelopmental disorder.

    View details for DOI 10.1016/j.neuron.2016.09.019

    View details for PubMedID 27693255

  • High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level NATURE COMMUNICATIONS Gong, H., Xu, D., Yuan, J., Li, X., Guo, C., Peng, J., Li, Y., Schwarz, L. A., Li, A., Hu, B., Xiong, B., Sun, Q., Zhang, Y., Liu, J., Zhong, Q., Xu, T., Zeng, S., Luo, Q. 2016; 7

    Abstract

    The precise annotation and accurate identification of neural structures are prerequisites for studying mammalian brain function. The orientation of neurons and neural circuits is usually determined by mapping brain images to coarse axial-sampling planar reference atlases. However, individual differences at the cellular level likely lead to position errors and an inability to orient neural projections at single-cell resolution. Here, we present a high-throughput precision imaging method that can acquire a co-localized brain-wide data set of both fluorescent-labelled neurons and counterstained cell bodies at a voxel size of 0.32 × 0.32 × 2.0 μm in 3 days for a single mouse brain. We acquire mouse whole-brain imaging data sets of multiple types of neurons and projections with anatomical annotation at single-neuron resolution. The results show that the simultaneous acquisition of labelled neural structures and cytoarchitecture reference in the same brain greatly facilitates precise tracing of long-range projections and accurate locating of nuclei.

    View details for DOI 10.1038/ncomms12142

    View details for Web of Science ID 000379912000001

    View details for PubMedID 27374071

  • Organization of the Locus Coeruleus-Norepinephrine System CURRENT BIOLOGY Schwarz, L. A., Luo, L. 2015; 25 (21): R1051-R1056

    Abstract

    The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors. Furthermore, disruption of norepinephrine-mediated signaling is strongly associated with several psychiatric and neurodegenerative disorders in humans, emphasizing the clinical importance of this system. Most of the norepinephrine released in the brain is supplied by a very small, bilateral nucleus in the brainstem called the locus coeruleus. The goal of this minireview is to emphasize the complexity of the locus coeruleus beyond its primary definition as a norepinephrine-producing nucleus. Several recent studies utilizing innovative technologies highlight how the locus coeruleus-norepinephrine system can now be targeted with increased accuracy and resolution, in order to better understand its role in modulating diverse behaviors.

    View details for DOI 10.1016/j.cub.2015.09.039

    View details for Web of Science ID 000364262500015

    View details for PubMedID 26528750

  • Viral-genetic tracing of the input-output organization of a central noradrenaline circuit. Nature Schwarz, L. A., Miyamichi, K., Gao, X. J., Beier, K. T., Weissbourd, B., DeLoach, K. E., Ren, J., Ibanes, S., Malenka, R. C., Kremer, E. J., Luo, L. 2015; 524 (7563): 88-92

    Abstract

    Deciphering how neural circuits are anatomically organized with regard to input and output is instrumental in understanding how the brain processes information. For example, locus coeruleus noradrenaline (also known as norepinephrine) (LC-NE) neurons receive input from and send output to broad regions of the brain and spinal cord, and regulate diverse functions including arousal, attention, mood and sensory gating. However, it is unclear how LC-NE neurons divide up their brain-wide projection patterns and whether different LC-NE neurons receive differential input. Here we developed a set of viral-genetic tools to quantitatively analyse the input-output relationship of neural circuits, and applied these tools to dissect the LC-NE circuit in mice. Rabies-virus-based input mapping indicated that LC-NE neurons receive convergent synaptic input from many regions previously identified as sending axons to the locus coeruleus, as well as from newly identified presynaptic partners, including cerebellar Purkinje cells. The 'tracing the relationship between input and output' method (or TRIO method) enables trans-synaptic input tracing from specific subsets of neurons based on their projection and cell type. We found that LC-NE neurons projecting to diverse output regions receive mostly similar input. Projection-based viral labelling revealed that LC-NE neurons projecting to one output region also project to all brain regions we examined. Thus, the LC-NE circuit overall integrates information from, and broadcasts to, many brain regions, consistent with its primary role in regulating brain states. At the same time, we uncovered several levels of specificity in certain LC-NE sub-circuits. These tools for mapping output architecture and input-output relationship are applicable to other neuronal circuits and organisms. More broadly, our viral-genetic approaches provide an efficient intersectional means to target neuronal populations based on cell type and projection pattern.

    View details for DOI 10.1038/nature14600

    View details for PubMedID 26131933

  • Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping CELL Beier, K. T., Steinberg, E. E., DeLoach, K. E., Xie, S., Miyamichi, K., Schwarz, L., Gao, X. J., Kremer, E. J., Malenka, R. C., Luo, L. 2015; 162 (3): 622-634
  • Synaptic Strength Is Bidirectionally Controlled by Opposing Activity-Dependent Regulation of Nedd4-1 and USP8 JOURNAL OF NEUROSCIENCE Scudder, S. L., Goo, M. S., Cartier, A. E., Molteni, A., Schwarz, L. A., Wright, R., Patrick, G. N. 2014; 34 (50): 16637-16649

    Abstract

    The trafficking of AMPA receptors (AMPARs) to and from synapses is crucial for synaptic plasticity. Previous work has demonstrated that AMPARs undergo activity-dependent ubiquitination by the E3 ubiquitin ligase Nedd4-1, which promotes their internalization and degradation in lysosomes. Here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of AMPARs. We report that Nedd4-1 is rapidly redistributed to dendritic spines in response to AMPAR activation and not in response to NMDA receptor (NMDAR) activation in cultured rat neurons. In contrast, NMDAR activation directly antagonizes Nedd4-1 function by promoting the deubiquitination of AMPARs. We show that NMDAR activation causes the rapid dephosphorylation and activation of the deubiquitinating enzyme (DUB) USP8. Surface AMPAR levels and synaptic strength are inversely regulated by Nedd4-1 and USP8. Strikingly, we show that homeostatic downscaling of synaptic strength is accompanied by an increase and decrease in Nedd4-1 and USP8 protein levels, respectively. Furthermore, we show that Nedd4-1 is required for homeostatic loss of surface AMPARs and downscaling of synaptic strength. This study provides the first mechanistic evidence for rapid and opposing activity-dependent control of a ubiquitin ligase and DUB at mammalian CNS synapses. We propose that the dynamic regulation of these opposing forces is critical in maintaining synapses and scaling them during homeostatic plasticity.

    View details for DOI 10.1523/JNEUROSCI.2452-14.2014

    View details for Web of Science ID 000346191500011

    View details for PubMedID 25505317

  • Ubiquitin-dependent endocytosis, trafficking and turnover of neuronal membrane proteins MOLECULAR AND CELLULAR NEUROSCIENCE Schwarz, L. A., Patrick, G. N. 2012; 49 (3): 387-393

    Abstract

    Extracellular signaling between cells is often transduced via receptors that reside at the cell membrane. In neurons this receptor-mediated signaling can promote a variety of cellular events such as differentiation, axon outgrowth and guidance, and synaptic development and function. Endocytic membrane trafficking of receptors ensures that the strength and duration of an extracellular signal is properly regulated. The covalent modification of membrane proteins by ubiquitin is a key biological mechanism controlling receptor internalization and endocytic sorting to recycling and degradative pathways in many cell types. In this review we highlight recent findings regarding the ubiquitin-dependent trafficking and turnover of receptors in neurons and the implications for neuronal development and function.

    View details for DOI 10.1016/j.mcn.2011.08.006

    View details for Web of Science ID 000302202100014

    View details for PubMedID 21884797

  • Activity-Dependent Ubiquitination of GluA1 Mediates a Distinct AMPA Receptor Endocytosis and Sorting Pathway JOURNAL OF NEUROSCIENCE Schwarz, L. A., Hall, B. J., Patrick, G. N. 2010; 30 (49): 16718-16729

    Abstract

    The accurate trafficking of AMPA receptors (AMPARs) to and from the synapse is a critical component of learning and memory in the brain, whereas dysfunction of AMPAR trafficking is hypothesized to be an underlying mechanism of Alzheimer's disease. Previous work has shown that ubiquitination of integral membrane proteins is a common posttranslational modification used to mediate endocytosis and endocytic sorting of surface proteins in eukaryotic cells. Here we report that mammalian AMPARs become ubiquitinated in response to their activation. Using a mutant of GluA1 that is unable to be ubiquitinated at lysines on its C-terminus, we demonstrate that ubiquitination is required for internalization of surface AMPARs and their trafficking to the lysosome in response to the AMPAR agonist AMPA but not for internalization of AMPARs in response to the NMDA receptor agonist NMDA. Through overexpression or RNA interference-mediated knockdown, we identify that a specific E3 ligase, Nedd4-1 (neural-precursor cell-expressed developmentally downregulated gene 4-1), is necessary for this process. Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature. Together, these data show that ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome. Furthermore, these results provide insight into how hippocampal neurons regulate AMPAR trafficking and degradation with high specificity in response to differing neuronal signaling cues and suggest that changes to this pathway may occur as neurons mature.

    View details for DOI 10.1523/JNEUROSCI.3686-10.2010

    View details for Web of Science ID 000285089100033

    View details for PubMedID 21148011

  • Regulation of the Proteasome by Neuronal Activity and Calcium/Calmodulin-dependent Protein Kinase II JOURNAL OF BIOLOGICAL CHEMISTRY Djakovic, S. N., Schwarz, L. A., Barylko, B., DeMartino, G. N., Patrick, G. N. 2009; 284 (39): 26655-26665

    Abstract

    Protein degradation via the ubiquitin proteasome system has been shown to regulate changes in synaptic strength that underlie multiple forms of synaptic plasticity. It is plausible, therefore, that the ubiquitin proteasome system is itself regulated by synaptic activity. By utilizing live-cell imaging strategies we report the rapid and dynamic regulation of the proteasome in hippocampal neurons by synaptic activity. We find that the blockade of action potentials (APs) with tetrodotoxin inhibited the activity of the proteasome, whereas the up-regulation of APs with bicuculline dramatically increased the activity of the proteasome. In addition, the regulation of the proteasome is dependent upon external calcium entry in part through N-methyl-D-aspartate receptors and L-type voltage-gated calcium channels and requires the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). Using in vitro and in vivo assays we find that CaMKII stimulates proteasome activity and directly phosphorylates Rpt6, a subunit of the 19 S (PA700) subcomplex of the 26 S proteasome. Our data provide a novel mechanism whereby CaMKII may regulate the proteasome in neurons to facilitate remodeling of synaptic connections through protein degradation.

    View details for DOI 10.1074/jbc.M109.021956

    View details for Web of Science ID 000269969600046

    View details for PubMedID 19638347