Yu-Tien Hsu received her Ph.D. in Neuroscience from University of Southern California under the mentorship of Dr. Michel Baudry to study the molecular mechanisms underlying learning and memory. To explore more precise and versatile tools for in vivo control of synaptic activity, she conducted post-doctoral research with Dr. Lu Chen at Stanford University and investigated behavioral and neural correlates of experience-dependent cognitive performance.

Current Role at Stanford

Research Scientist

Education & Certifications

  • Ph.D., University of Southern California, Neuroscience (2011)


All Publications

  • Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hsu, Y., Li, J., Wu, D., Sudhof, T. C., Chen, L. 2019; 116 (14): 7113?22
  • Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning. Proceedings of the National Academy of Sciences of the United States of America Hsu, Y., Li, J., Wu, D., Sudhof, T. C., Chen, L. 2019


    Homeostatic synaptic plasticity is a stabilizing mechanism engaged by neural circuits in response to prolonged perturbation of network activity. The non-Hebbian nature of homeostatic synaptic plasticity is thought to contribute to network stability by preventing "runaway" Hebbian plasticity at individual synapses. However, whether blocking homeostatic synaptic plasticity indeed induces runaway Hebbian plasticity in an intact neural circuit has not been explored. Furthermore, how compromised homeostatic synaptic plasticity impacts animal learning remains unclear. Here, we show in mice that the experience of an enriched environment (EE) engaged homeostatic synaptic plasticity in hippocampal circuits, thereby reducing excitatory synaptic transmission. This process required RARalpha, a nuclear retinoic acid receptor that doubles as a cytoplasmic retinoic acid-induced postsynaptic regulator of protein synthesis. Blocking RARalpha-dependent homeostatic synaptic plasticity during an EE experience by ablating RARalpha signaling induced runaway Hebbian plasticity, as evidenced by greatly enhanced long-term potentiation (LTP). As a consequence, RARalpha deletion in hippocampal circuits during an EE experience resulted in enhanced spatial learning but suppressed learning flexibility. In the absence of RARalpha, moreover, EE experience superactivated mammalian target of rapamycin (mTOR) signaling, causing a shift in protein translation that enhanced the expression levels of AMPA-type glutamate receptors. Treatment of mice with the mTOR inhibitor rapamycin during an EE experience not only restored normal AMPA-receptor expression levels but also reversed the increases in runaway Hebbian plasticity and learning after hippocampal RARalpha deletion. Thus, our findings reveal an RARalpha- and mTOR-dependent mechanism by which homeostatic plasticity controls Hebbian plasticity and learning.

    View details for PubMedID 30782829

  • A metaplasticity view of the interaction between homeostatic and Hebbian plasticity PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Yee, A. X., Hsu, Y., Chen, L. 2017; 372 (1715)


    Hebbian and homeostatic plasticity are two major forms of plasticity in the nervous system: Hebbian plasticity provides a synaptic basis for associative learning, whereas homeostatic plasticity serves to stabilize network activity. While achieving seemingly very different goals, these two types of plasticity interact functionally through overlapping elements in their respective mechanisms. Here, we review studies conducted in the mammalian central nervous system, summarize known circuit and molecular mechanisms of homeostatic plasticity, and compare these mechanisms with those that mediate Hebbian plasticity. We end with a discussion of 'local' homeostatic plasticity and the potential role of local homeostatic plasticity as a form of metaplasticity that modulates a neuron's future capacity for Hebbian plasticity.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'.

    View details for DOI 10.1098/rstb.2016.0155

    View details for Web of Science ID 000393410000005

    View details for PubMedID 28093549

    View details for PubMedCentralID PMC5247587

  • Conditional knockout of Nlgn2 in the adult medial prefrontal cortex (mPFC) induces delayed loss of inhibitory synapses. Molecular psychiatry Liang, J., Xu, W., Hsu, Y., Yee, A. X., Chen, L., Südhof, T. C. 2015; 20 (7): 793-?

    View details for DOI 10.1038/mp.2015.82

    View details for PubMedID 26098222

  • Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments MOLECULAR PSYCHIATRY Liang, J., Xu, W., Hsu, Y., Yee, A. X., Chen, L., Suedhof, T. C. 2015; 20 (7): 850?59


    Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.

    View details for PubMedID 25824299

  • A molecular brake controls the magnitude of long-term potentiation. Nature communications Wang, Y., Zhu, G., Briz, V., Hsu, Y., Bi, X., Baudry, M. 2014; 5: 3051-?


    Overexpression of suprachiasmatic nucleus circadian oscillatory protein (SCOP), a negative ERK regulator, blocks long-term memory encoding. Inhibition of calpain-mediated SCOP degradation also prevents the formation of long-term memory, suggesting rapid SCOP breakdown is necessary for memory encoding. However, whether SCOP levels also control the magnitude of long-term synaptic plasticity is unknown. Here we show that following synaptic activity-induced SCOP degradation, SCOP is rapidly replaced via mTOR-mediated protein synthesis. We further show that early SCOP degradation is specifically catalysed by ?-calpain, whereas late SCOP resynthesis is mediated by m-calpain. We propose that ?-calpain promotes long-term potentiation induction by degrading SCOP and activating ERK, whereas m-calpain activation limits the magnitude of potentiation by terminating the ERK response via enhanced SCOP synthesis. This unique braking mechanism could account for the advantages of spaced versus massed training in the formation of long-term memory.

    View details for DOI 10.1038/ncomms4051

    View details for PubMedID 24394804

    View details for PubMedCentralID PMC3895372

  • Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis. The Journal of neuroscience : the official journal of the Society for Neuroscience Briz, V., Hsu, Y. T., Li, Y., Lee, E., Bi, X., Baudry, M. 2013; 33 (10): 4317?28


    Memory consolidation has been suggested to be protein synthesis dependent. Previous data indicate that BDNF-induced dendritic protein synthesis is a key event in memory formation through activation of the mammalian target of rapamycin (mTOR) pathway. BDNF also activates calpain, a calcium-dependent cysteine protease, which has been shown to play a critical role in learning and memory. This study was therefore directed at testing the hypothesis that calpain activity is required for BDNF-stimulated local protein synthesis, and at identifying the underlying molecular mechanism. In rat hippocampal slices, cortical synaptoneurosomes, and cultured neurons, BDNF-induced mTOR pathway activation and protein translation were blocked by calpain inhibition. BDNF treatment rapidly reduced levels of hamartin and tuberin, negative regulators of mTOR, in a calpain-dependent manner. Treatment of brain homogenates with purified calpain-1 and calpain-2 truncated both proteins. BDNF treatment increased phosphorylation of both Akt and ERK, but only the effect on Akt was blocked by calpain inhibition. Levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect. Calpain-2, but not calpain-1, treatment of brain homogenates resulted in PTEN degradation. In cultured cortical neurons, knockdown of calpain-2, but not calpain-1, by small interfering RNA completely suppressed the effect of BDNF on mTOR activation. Our results reveal a critical role for calpain-2 in BDNF-induced mTOR signaling and dendritic protein synthesis via PTEN, hamartin, and tuberin degradation. This mechanism therefore provides a link between proteolysis and protein synthesis that might contribute to synaptic plasticity.

    View details for DOI 10.1523/JNEUROSCI.4907-12.2013

    View details for PubMedID 23467348

    View details for PubMedCentralID PMC3657575

  • The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. Neuropharmacology Hsu, Y. T., Liao, G., Bi, X., Oka, T., Tamura, S., Baudry, M. 2011; 61 (8): 1275?81


    The phosphodiesterase 10A (PDE10A) is highly expressed within dopaminoreceptive medium spiny neurons (MSNs) of the striatum, which are implicated in various neurodegenerative diseases and psychiatric disorders, such as Huntington's disease and schizophrenia. With its dual action on cAMP and cGMP, PDE10A has been proposed to affect several signaling cascades in the corticostriatothalamic circuits. In particular, papaverine, a selective PDE10A inhibitor has been shown to activate/phosphorylate ERK in striatum. We used acute rat striatal slices to further characterize the effects of papaverine on ERK activation/phosphorylation in D1- and D2-responsive striatal neurons. Incubation of striatal slices from male rats with papaverine increased the levels of phospho-ERK1/2 (p-ERK), an effect enhanced with a D1 agonist or a D2 antagonist, but decreased with a D1 receptor antagonist or a D2 receptor agonist. Papaverine-induced increase in p-ERK was localized in striatal neurons receiving D1-enriched presynaptic terminals, as well as in postsynaptic D2-enriched neurons in striatal slices. Interestingly, papaverine had almost no stimulatory effects on ERK1/2 phosphorylation in slices prepared from female rats. In striatal slices prepared from ovariectomized female rats, papaverine treatment stimulated ERK1/2 phosphorylation to levels similar to those in slices from male rats. Moreover, estrogen was found to regulate the levels of D2 but not D1 receptors in striatum. These results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Considering the variety of events modulated by ERK1/2 activity, these findings suggest that sex difference needs to be taken into consideration for the further investigation of the effects of PDE10A inhibitors.

    View details for DOI 10.1016/j.neuropharm.2011.07.030

    View details for PubMedID 21816164

  • Calpain-mediated regulation of stargazin in adult rat brain. Neuroscience Yu, L., Rostamiani, K., Hsu, Y. T., Wang, Y., Bi, X., Baudry, M. 2011; 178: 13?20


    Changes in AMPA receptors have been proposed to underlie changes in synaptic efficacy in hippocampus and other brain structures. Calpain activation has also been discussed as a potential mechanism to produce lasting modifications of synaptic structure and function. Stargazin is a member of the family of transmembrane AMPA receptor associated proteins (TARPs), which participates in trafficking of AMPA receptors and regulates their kinetic properties. We report here that preincubation of thin (20 ?m) frozen rat brain sections with calcium changes the immunological properties of stargazin, an effect totally blocked by a calpain inhibitor. Immunocytochemistry indicates that in situ calpain activation produces a decreased immunoreactivity for stargazin in the neuropil throughout the brain, and Western blots confirmed that a similar treatment decreased stargazin levels. Interestingly, the same treatment did not modify the immunoreactivity for another TARP member, ?-8, although it increased immunoreactivity in cell bodies in hippocampus, an effect that was not blocked by calpain inhibition. These results strongly suggest the involvement of calpain in the regulation of AMPA receptor targeting and function through truncation of stargazin.

    View details for DOI 10.1016/j.neuroscience.2011.01.026

    View details for PubMedID 21256931

    View details for PubMedCentralID PMC3049944

  • Glutamatergic neurons in rodent models respond to nanoscale particulate urban air pollutants in vivo and in vitro. Environmental health perspectives Morgan, T. E., Davis, D. A., Iwata, N., Tanner, J. A., Snyder, D., Ning, Z., Kam, W., Hsu, Y. T., Winkler, J. W., Chen, J. C., Petasis, N. A., Baudry, M., Sioutas, C., Finch, C. E. 2011; 119 (7): 1003?9


    Inhalation of airborne particulate matter (PM) derived from urban traffic is associated with pathology in the arteries, heart, and lung; effects on brain are also indicated but are less documented.We evaluated rodent brain responses to urban nanoscale (< 200 nm) PM (nPM).Ambient nPM collected near an urban freeway was transferred to aqueous suspension and reaerosolized for 10-week inhalation exposure of mice or directly applied to rat brain cell cultures.Free radicals were detected by electron paramagnetic resonance in the nPM 30 days after initial collection. Chronic inhalation of reaerosolized nPM altered selected neuronal and glial activities in mice. The neuronal glutamate receptor subunit (GluA1) was decreased in hippocampus, whereas glia were activated and inflammatory cytokines were induced [interleukin-1? (IL-1?), tumor necrosis factor-? (TNF?)] in cerebral cortex. Two in vitro models showed effects of nPM suspensions within 24-48 hr of exposure that involved glutamatergic functions. In hippocampal slice cultures, nPM increased the neurotoxicity of NMDA (N-methyl-d-aspartic acid), a glutamatergic agonist, which was in turn blocked by the NMDA antagonist AP5 [(2R)-amino-5-phosphonopentanoate]. In embryonic neuron cultures, nPM impaired neurite outgrowth, also blocked by AP5. Induction of IL-1? and TNF? in mixed glia cultures required higher nPM concentrations than did neuronal effects. Because conditioned media from nPM-exposed glia also impaired outgrowth of embryonic neurites, nPM can act indirectly, as well as directly, on neurons in vitro.nPM can affect embryonic and adult neurons through glutamatergic mechanisms. The interactions of nPM with glutamatergic neuronal functions suggest that cerebral ischemia, which involves glutamatergic excitotoxicity, could be exacerbated by nPM.

    View details for DOI 10.1289/ehp.1002973

    View details for PubMedID 21724521

    View details for PubMedCentralID PMC3222976

  • Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. The Journal of neuroscience : the official journal of the Society for Neuroscience Jourdi, H., Hsu, Y. T., Zhou, M., Qin, Q., Bi, X., Baudry, M. 2009; 29 (27): 8688?97


    Brain-derived neurotrophic factor (BDNF) stimulates local dendritic mRNA translation and is involved in formation and consolidation of memory. 2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan-10-one (CX614), one of the best-studied positive AMPA receptor modulators (also known as ampakines), increases BDNF mRNA and protein and facilitates long-term potentiation (LTP) induction. Several other ampakines also improve performance in various behavioral and learning tasks. Since local dendritic protein synthesis has been implicated in LTP stabilization and in memory consolidation, this study investigated whether CX614 could influence synaptic plasticity by upregulating dendritic protein translation. CX614 treatment of primary neuronal cultures and acute hippocampal slices rapidly activated the translation machinery and increased local dendritic protein synthesis. CX614-induced activation of translation was blocked by K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], CNQX, APV, and TTX, and was inhibited in the presence of an extracellular BDNF scavenger, TrkB-Fc. The acute effect of CX614 on translation was mediated by increased BDNF release as demonstrated with a BDNF scavenging assay using TrkB-Fc during CX614 treatment of cultured primary neurons and was blocked by nifedipine, ryanodine, and lack of extracellular Ca(2+) in acute hippocampal slices. Finally, CX614, like BDNF, rapidly increased dendritic translation of an exogenous translation reporter. Together, our results demonstrate that positive modulation of AMPA receptors rapidly stimulates dendritic translation, an effect mediated by BDNF secretion and TrkB receptor activation. They also suggest that increased BDNF secretion and stimulation of local protein synthesis contribute to the effects of ampakines on synaptic plasticity.

    View details for DOI 10.1523/JNEUROSCI.6078-08.2009

    View details for PubMedID 19587275

    View details for PubMedCentralID PMC2761758

  • Evaluation of [F-18]gefitinib as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in malignant tumors EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Su, H., Seimbille, Y., Ferl, G. Z., Bodenstein, C., Fueger, B., Kim, K. J., Hsu, Y., Dubinett, S. M., Phelps, M. E., Czernin, J., Weber, W. A. 2008; 35 (6): 1089?99


    Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK), has shown potent effects in a subset of patients carrying specific EGFR-TK mutations in advanced non-small-cell lung cancer. In this study, we asked whether PET with [(18)F]gefitinib may be used to study noninvasively the pharmacokinetics of gefitinib in vivo and to image the EGFR status of cancer cells.Synthesis of [(18)F]gefitinib has been previously described. The biodistribution and metabolic stability of [(18)F]gefitinib was assessed in mice and vervet monkeys for up to 2 h post injection by both micropositron emission tomography (PET)/computed tomography (CT) scans and postmortem ex vivo tissue harvesting. Uptake levels of radiolabeled gefitinib in EGFR-expressing human cancer cell lines with various levels of EGFR expression or mutation status were evaluated both in vivo and in vitro.MicroPET/CT scans in two species demonstrated a rapid and predominantly hepatobiliary clearance of [(18)F]gefitinib in vivo. However, uptake levels of radiolabeled gefitinib, both in vivo and in vitro, did not correlate with EGFR expression levels or functional status. This unexpected observation was due to high nonspecific, nonsaturable cellular uptake of gefitinib.The biodistribution of the drug analogue [(18)F]gefitinib suggests that it may be used to assess noninvasively the pharmacokinetics of gefitinib in patients by PET imaging. This is of clinical relevance, as insufficient intratumoral drug concentrations are considered to be a factor for resistance to gefitinib therapy. However, the highly nonspecific cellular binding of [(18)F]gefitinib may preclude the use of this imaging probe for noninvasive assessment of EGFR receptor status in patients.

    View details for DOI 10.1007/s00259-007-0636-6

    View details for Web of Science ID 000255856800007

    View details for PubMedID 18239919

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