Areas of Research:

• Functional plasticity in the juvenile and adolescent prefrontal cortex and cognitive functions associated with this cortical region
• Cellular and synaptic mechanisms of neuronal network activity in the prefrontal cortex
• Molecular and cellular mechanisms underlying synaptic transmission and monoaminergic regulation of the prefrontal function
• Neurobiology of psychiatric disorders associated with the prefrontal cortex and limbic systems, such as schizophrenia, autism and ADHD

Lab Personnel:

• Graduate Students: Alexander Benson; Jake Clarin; Volodar Migovich
• MD/PhD Student: Leigh Taylor Flynn
• Drexel Student: Nadia Bouras

Visit the Gao Lab

Research Summary

The cerebral cortex, especially the prefrontal cortex, is the most complex brain region in the central nervous system. Elucidating its diverse functions represents a major challenge in neurobiology. We are interested in the neuronal mechanisms underlying the synaptic signaling and monoaminergic regulation in the prefrontal cortical circuitry, as well as the critical issues involving neuropathology of mental disorders and other neurological diseases. Specifically, we are taking the advantages of in vivo and in vitro preparations to examine the neuronal signaling in both normal animals and clinical models of psychiatric disorders, such as schizophrenia and ADHD.

Work in the laboratory is currently focused in the following projects:

1. Monoaminergic (dopamine and norepinephrine) regulation of synaptic transmissions and local circuitry in the prefrontal cortex
2. How high-risk genes or epigenetic factors associated with schizophrenia affect the development of prefrontal cortex
3. The roles of NMDA receptors in the schizophrenia pathological process
4. Psychostimulant actions on the synaptic plasticity and trafficking of glutamatergic receptors.

Our research involves a variety of morphological, physiological, pharmacological, and molecular approaches designed to elucidate the synaptic mechanisms underlying the prefrontal functions. Morphological studies include single-cell labeling, neuronal reconstruction, and immunocytochemistry. Physiological, pharmacological and molecular approaches include multiple whole-cell patch clamp recordings, drug applications, western blotting, and real-time PCR in fresh brain tissues, acute brain slices, and cell culture preparations. These approaches are mutually supportive with a comprehensive integration across disciplines.

Selected Grants Funded

NIH R01MH085666 (Gao, PI)
Role of NMDA receptors in schizophrenia pathological processes

NIH R01MH101178 (Barry Waterhouse, PI; Gao, co-PI,)
Phenotypic diversity of neurons modulating executive function

NARSAD Independent Investigator Award, 2015 (Gao, PI)
Augmenting inhibition for cognitive function in schizophrenia

NIH R21MH110678-01 (Gao, PI)
Role of prefrontal cortical dopamine in aggression

Drexel Interdisciplinary Program Initiative/Pennsylvania Department of Health (Gao, PI; Barry Waterhouse, co-PI) CURE grant
Prefrontal cortical control of social behavior and aggression

Drexel Interdisciplinary Program Initiative/Pennsylvania Department of Health (Gao, co-PI; Denise Garcia, PI) CURE grant
The role of astrocytic Sonic hedgehog signaling in cortical circuit development

Commonwealth of Pennsylvania Announces Recent CURE Grant Recipients
(August 14, 2023)

"Inside the Brain: The Wiring of Addiction"
Exel, Drexel's Research Magazine (2014)

"Bad News For Ivy Leaguers: ADHD Drugs Hurt Your Memory"
Time, Examiner, Fox News (May 13, 2014)

"Taking 'Smart Drugs' Not Such a Bright Idea According to New Research"
College of Medicine Newsroom (May 13, 2014)

Selected/Recent Publications

“The role of cell adhesion molecule IgSF9b at the inhibitory synapse and psychiatric disease”
Clarin JD, Reddy N, Alexandropoulos C, Gao WJ
Neurosci Biobehav Rev. 2024 Jan;156:105476. doi: 10.1016/j.neubiorev.2023.105476. Epub 2023 Nov 29. PMID: 38029609

“DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness”
Flynn LT, Gao WJ
Mol Psychiatry. 2023 Sep 7. doi: 10.1038/s41380-023-02235-4. Online ahead of print. PMID: 37679470

“Pharmacogenetic activation of parvalbumin interneurons in the prefrontal cortex rescues cognitive deficits induced by adolescent MK801 administration”
Linda A. Chamberlin1, 2, Sha-Sha Yang1, 3, Erin P. McEachern1, Joshua T. M. Lucas4, Owen W. McLeod II5, Claire A. Rolland5, Nancy R. Mack1, Brielle R. Ferguson1, 6, Wen-Jun Gao1
Neuropsychopharmacology. 2023 Apr 11. PMID: 37041206 DOI: 10.1038/s41386-023-01576-6 (2023)

“Prefrontal modulation of anxiety through a lens of noradrenergic signaling”
Nadia N. Bouras, Nancy R. Mack*, and Wen-Jun Gao*
Frontiers in Systems Neuroscience (2023)

"Prepubertal environment enrichment prevents psychosis-related dopamine dysregulation in a neurodevelopmental model for schizophrenia"
Nancy R. Mack and Wen-Jun Gao
Biological Psychiatry, 89(3):212-214. (2021, commentary)

"From hyposociability to hypersociability -the effects of PSD-95 deficiency on the dysfunctional development of social behavior"
Wen-Jun Gao* and Nancy R. Mack
Frontiers in Behavioral Neuroscience, 28 January 2021 | https://doi.org/10.3389/fnbeh.2021.618397. (2021, perspective)

• *Commentary: April Pruitt and AZA Stephen Allsop (2021): Understanding the Role of a Molecularly Defined Social Circuit. Biological Psychiatry, 89(5):421-423

"Aberrant maturation and connectivity of prefrontal cortex in schizophrenia – contribution of NMDA receptor development and hypofunction"
Wen-Jun Gao, Sha-Sha Yang, Nancy R. Mack, and Linda A. Chamberlin
Molecular Psychiatry. (2021, invited Expert Review)

"Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors" Sha-Sha Yang, Nancy R. Mack, Yousheng Shu and Wen-Jun Gao*
Front. Neural Circuits. 15: 716408 (2021, invited review)

"Distinct roles for prefrontal dopamine D1 and D2 neurons in social hierarchy"
Bo Xing#, Nancy R. Mack#, Yu-Xiang Zhang, Erin P. McEachern and Wen-Jun Gao
The Journal of Neuroscience, In press. (2021)

"A subpopulation of prefrontal cortical neurons is required for social memory"
Bo Xing1, Nancy R. Mack1, Kai-Ming Guo2,3, Yu-Xiang Zhang1, Billy Ramirez1, Sha-Sha Yang1, Li Lin2*, Dong V. Wang1, Yan-Chun Li1, and Wen-Jun Gao1*
Biological Psychiatry (accepted). Biological Psychiatry, 89(5):521-531. September 04, 2020DOI:https://doi.org/10.1016/j.biopsych.2020.08.023 (2021)

"PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex"
Erin P. McEachern, Austin A. Coley, Sha-Sha Yang, Wen-Jun Gao
Neuropharmacology, available online 18 August 2020, 108277. (2020)

"The Paraventricular Nucleus of the Thalamus is an Important Node in the Emotional Processing Network"
Jessica R. Barson, Nancy R. Mack, Wen-Jun Gao
Frontiers in Behavioral Neuroscience, section Emotion Regulation and Processing. 14:191 (2020, invited review)

"Deletion of GSK-3β in D2R-expressing neurons ameliorates cognitive impairment via NMDAR-dependent synaptic plasticity"
Yan-Chun Li, Priyalakshmi Panikker, Bo Xing, Sha-Sha Yang, Cassandra Alexandropoulos, Erin P McEachern, Rita Akumuo, Elise Zhao, Yelena Gulchina, Mikhail V. Pletnikov, Nikhil M. Urs, Marc G. Caron, Felice Elefant, and Wen-Jun Gao
Biological Psychiatry. 87:745-755. pii: S0006-3223(19)31828-1. doi: 10.1016/j.biopsych.2019.10.025. [Epub ahead of print] PMID: 31892408 (2020)

• Commentary: "Epigenetic Mechanism Links NMDA Receptor Hypofunction and Cognitive Deficits in Schizophrenia to D2 Receptors"
  Michael F. Jackson
  Biological Psychiatry, 87:692-694

"Conditional GSK3β deletion in parvalbumin-expressing interneurons potentiates excitatory synaptic function and learning in adult mice"
Monaco SA, Matamoros AJ, Gao WJ
Prog Neuropsychopharmacol Biol Psychiatry;100:109901. doi: 10.1016/j.pnpbp.2020.109901 (Epub Feb 27, 2020) Jun 8, 2020

"PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment"
Austin Coley and Wen-Jun Gao
Scientific Reports, 9:9486 (July 1, 2019)

"Sonic hedgehog signaling in astrocytes mediates cell-type specific synaptic organization"
Steven Hill, Andrew Blaeser, Austin A. Coley, Katherine A. Shepard, Corey Harwell, Wen-Jun Gao, A. Denise R. Garcia
eLife; [Epub ahead of print] 8. pii: e45545. doi: 10.7554/eLife.45545 (Jun 13, 2019)

Invited review: "NMDA receptor hypofunction for schizophrenia revisited: Perspectives from epigenetic mechanisms"
Melissa A. Snyder and Wen-Jun Gao
Schizophrenia Research. [Epub ahead of print] pii: S0920-9964(19)30104-5. doi: 10.1016/j.schres.2019.03.010 (Apr 9, 2019)

"Selective vulnerability of dorsal raphe-medial prefrontal cortex projection neurons to corticosterone-induced hypofunction"
Prouty EW, Chandler DJ, Gao WJ, Waterhouse BD
Eur J Neurosci. [Epub ahead of print] PubMed PMID: 30687960 (Jan 28, 2019)

"Neurons in rat orbitofrontal cortex and medial prefrontal cortex exhibit distinct responses in reward and strategy-update in a risk-based decision-making task"
Dan-Dan Hong, Wen-Qiang Huang, Ai-Ai Ji, Sha-Sha Yang, Hui Xu, Ke-Yi Sun, Aihua Cao, Wen-Jun Gao, Ning Zhou*, Ping Yu*
Metabolic Brain Disease, 34(2):417-429, Epub 2018 Dec 8, PubMed PMID: 30535618 (Apr 2019)

"Absence of associative motor learning and impaired time perception in a rare case of complete cerebellar agenesis"
Bing Wu, Juan Yao, Guang-yan Wu, Xuang Li, Wen-Jun Gao*, Rong Wei*, Jian-Feng Sui*
(*corresponding authors)
Neuropsychologia, 117-551-557.  PMID: 30031016 (2018)

"The histone demethylase KDM6B in the medial prefrontal cortex epigenetically regulates cocaine reward memory"
Yu-Xiang Zhang, Rita C. Akumuo, Rodrigo A. España, Chun-Xia Yan*, Wen-Jun Gao*, and Yan-Chun Li*
(*corresponding authors)
Neuropharmacology, 141: 113-125.  PMID: 30165076 (2018)

"Juvenile treatment with mGluR2/3 agonist prevents schizophrenia-like phenotypes in adult by acting through GSK3b"
Xing B, Han G, Wang MJ, Snyder MA, Gao WJ
Neuropharmacology, 137:359-371 (2018)

"Cell-type specific development of the hyperpolarization-activated current, Ih, in prefrontal cortical neurons"
Yang SS, Li YC, Coley AA, Chamberlin LA, Yu P*, Gao WJ*
Frontiers in Synaptic Neuroscience 10(7):1-12 (2018)

"PV interneurons: critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders"
Ferguson BR and Gao WJ*
Frontiers in Neural Circuits. 12:37 (2018)

"Lithium Inhibits GSK3β and Augments GluN2A Receptor Expression in the Prefrontal Cortex"
Sarah A. Monaco, Brielle R. Ferguson and Wen-Jun Gao*
Front. Cell. Neurosci., February 1, 2018

"Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex"
Ferguson BR, Gao WJ
Biol Psychiatry. pii: S0006-3223(17)32256-4. doi: 10.1016/j.biopsych.2017.11.033, PubMed PMID: 29373121 [Epub ahead of print] Dec 7, 2017

"PSD95: A synaptic protein implicated in schizophrenia or autism?"
Coley AA, Gao WJ
Prog Neuropsychopharmacol Biol Psychiatry.;82:187-194. doi: 10.1016/j.pnpbp.2017.11.016. Review. PubMed PMID: 29169997. Mar 2, 2018, Epub Nov 21, 2017

"Psychostimulants As Cognitive Enhancers in Adolescents: More Risk than Reward?"
Urban KR, Gao WJ
Front Public Health; 5:260. doi: 10.3389/fpubh.2017.00260. eCollection 2017. Review. PubMed PMID: 29034227; PubMed Central PMCID: PMC5626934, Sep 26, 2017

"Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia"
Gulchina Y, Xu SJ, Snyder MA, Elefant F, Gao WJ
J Neurochem,.doi: 10.1111/jnc.14101. [Epub ahead of print] Jun 19, 2017

"A Clinically-Relevant Dose of Methylphenidate Enhances Synaptic Inhibition in the Juvenile Rat Prefrontal Cortex"
Kimberly Urban, Yan-Chun Li, Bo Xing, Wen-Jun Gao
Journal of Reward Deficiency Syndrome & Addiction Science, in press (2017)

"Juvenile Treatment with a Novel mGluR2 Agonist/mGluR3 Antagonist Compound, LY395756, Reverses Learning Deficits and Cognitive Flexibility Impairments in Adults in A Neurodevelopmental Model of Schizophrenia"
Meng-Lin Li, Yelena Gulchina, Sarah A. Monaco, Bo Xing, Brielle R. Ferguson, Yan-Chun Li, Feng Li, Xi-Quan Hu , Wen-Jun Gao
Neurobiology of Learning and Memory, 140:52-61 (2017)

"GSK3β hyperactivity during an early critical period impairs prefrontal synaptic plasticity and induces lasting deficits in spine morphology and working memory"
Bo Xing, Yan-Chun Li and Wen-Jun Gao
Neuropsychopharmacology, 41(13) (2016)

"Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex" [PDF]
Yan-Chun Li, Sha-sha Yang and Wen-Jun Gao
Neuropharmacology, 108:403-414 (2016)

"Norepinephrine versus Dopamine and their Interaction in Modulating Synaptic Function in the Prefrontal Cortex" [PDF]
Bo Xing, Yan-Chun Li and Wen-Jun Gao
Brain Research 1641 (Pt B):217-233 (invited review, 2016)

"LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment" [PDF]
Meng-Lin (Merry) Li, Shasha Yang, Bo Xing, Brielle Ferguson, Yelena Gulchina, Yan-chun Li, Feng Li*, Xi-Quan Hu* and Wen-Jun Gao*
Experimental Neurology 273:190-201 (2015)

"NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders" [PDF]
Sarah A. Monaco#, Yelena Gulchina# and Wen-Jun Gao (# These authors contributed equally)
Neuroscience and Biobehavioral Reviews 56:127-138 (2015)

"Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?" [PDF]
Meng-Lin (Merry) Li, Xi-Quan Hu, Feng Li and Wen-Jun Gao
Progress in Neuropsychopharmacology & Biological Psychiatry 60:66-76 (review, 2015)

"Development of thalamocortical connections between the mediodorsal nucleus of the thalamus and the prefrontal cortex and its implication in executive and cognitive function" [PDF]
Brielle R. Ferguson and Wen-Jun Gao
Frontiers in Human Neuroscience, 8(1027):1-10 (invited review, 2015)

"Heterogeneous Organization of the Locus Coeruleus Projections to Prefrontal and Motor Cortices" [PDF]
Daniel J. Chandler, Wen-Jun Gao and Barry D. Waterhouse
PNAS, 111(18):6816-6821 (2014)

"New Perspectives on Catecholaminergic Regulation of Executive Circuits: Evidence for Independent Modulation of Prefrontal Functions by Midbrain Dopaminergic and Noradrenergic Neurons" [PDF]
Daniel J. Chandler, Barry D. Waterhouse and Wen-Jun Gao
Frontiers in Neural Circuits, 8:53 (invited review, May 23, 2014)

"Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain" [PDF]
Kimberly R. Urban and Wen-Jun Gao
Frontiers in Systems Neuroscience, 8:38 (invited review, May 13, 2014)

"Gestational methylazoxymethanol (MAM) exposure leads to NMDAR dysfunction in hippocampus during early development and lasting deficits in learning"
Melissa A. Snyder, Alicia E. Adelman, and Wen-Jun Gao 
Neuropsychopharmacology, 38(2):328-40 (Jan 2013)

"Evolution of the Study of Methylphenidate and its Actions on the Adult versus Juvenile Brain"
Kimberly R. Urban and Wen-Jun Gao
Journal of Attention Disorders, published online (August 24, 2012)

"Hyperdopaminergic Modulation of Inhibitory Transmission Is Dependent on GSK-3β Signaling-Mediated Trafficking of GABAa Receptors"
Yan-Chun Li, Min-Juan Wang, and Wen-Jun Gao
Journal of Neurochemistry, 122(2):308-320 (July 2012)

"Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons"
Kimberly Urban, Barry Waterhouse, and Wen-Jun Gao
Biological Psychiatry, 72(10):880-8 (November 15, 2012)

"Prolonged exposure to NMDAR antagonist induces cell-type specific changes of glutamatergic receptors in rat prefrontal cortex"
Huai-Xing Wang and Wen-Jun Gao
Neuropharmacology 62:1808-1822 (2012)

"D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in prefrontal cortex"
Yan-Chun Li, Christoph Kellendonk , Eleanor H. Simpson, Eric R. Kandel, Wen-Jun Gao
PNAS, 108(29): 12107-112. Commentary in Schizophrenia Research Forum (2011)

"Experimental strategies for investigating drug actions in ADHD and related attention disorders"
Agster K, Clark B, Gao WJ, Shumsky J, Wang HX, Berridge C and Waterhouse B
Anatomical Record, 294:1698-1712 (invited review, 2011)

"Group II metabotropic glutamate receptor agonist ameliorates MK-801-induced dysfunction of NMDA receptors via Akt/GSK-3b pathway"
Dong Xi*, Yan-Chun Li*, Melissa A. Snyder*, Ruby Y. Gao, Alicia E. Adelman, Wentong Zhang, Jed S. Shumsky, and Wen-Jun Gao (*these authors contribute equally)
Neuropsychopharmacology. 36:1260-1274  (2011)

"GSK-3 and hyperdopaminergic behaviors"
Yan-Chun Li and Wen-Jun Gao
Neuroscience & Biobehavioral Reviews. 35:645-654 (2011)

"Development of calcium-permeable AMPA receptors and their correlation with NMDA receptors in fast-spiking interneurons of rat prefrontal cortex"
Huai-Xing Wang and Wen-Jun Gao
The Journal of Physiology, 588(15):2823-2838 (2010)
selected for Faculty of 1000 Medicine (www.f1000medicine.com) and evaluated by Dr. Antonio Pisani.

"Dopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons"
Jian-Li Hu*, Gang Liu*, Yan-Chun Li*, Wen-Jun Gao, Yue-Qiao Huang (*these authors contribute equally)
Molecular Brain, 3:20 (2010)

"Dopamine D1 receptor-mediated enhancement of NMDA receptor trafficking requires rapid PKC-dependent synaptic insertion in the prefrontal neurons"
Yan-Chun Li*, Gang Liu*, Jian-Li Hu*, Wen-Jun Gao* and Yue-Qiao Huang*  (*these authors contribute equally)
The Journal of Neurochemistry. 114:62-73  (2010)

"Activation of GSK-3b is required for hyperdopamine and D2 receptor mediated inhibition of synaptic NMDA receptor function in the rat prefrontal cortex"
Yan-Chun Li, Dong Xi, Joy Roman, Yue-Qiao Huang,  and Wen-Jun Gao
Journal of Neuroscience, 29(49):15551-15563 (2009)

"Role of dysbindin in dopamine receptor trafficking and cortical GABA function"
Ji Y, Yang F, Papaleo F, Wang HX, Gao WJ, Weinberger DR, Lu B
PNAS, 106:19593-19598 (2009)

"Dizocilpine (MK-801) induces distinct changes of N-methyl-d-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex"
Xi D , Zhang W, Wang HX, Stradtman GG III and Gao WJ
Int J Neuropsychopharmacol, 12:1395-1408 (2009)

"Cell-type specific development of NMDA receptors in the interneurons of rat prefrontal cortex"
Wang HX and Gao WJ
Neuropsychopharmacology, 34(8):2028-2040 (2009)

"NMDA receptor subunit expression in GABAergic interneurons in the prefrontal cortex: application of laser microdissection technique"
Xi D, Keeler B, Zhang W, Houle JD, and Gao WJ
Journal of Neuroscience Method, 176:172-181, 2009

"A specialized NMDA receptor function in the recurrent microcircuitry of the adult prefrontal cortex"
Wang HX, Stradtman GG III, Wang X-J, and Gao WJ
PNAS, 105(43):16791-16796, 2008

"Acute clozapine suppresses synchronized pyramidal synaptic network activity by increasing inhibition in the prefrontal cortex"
Gao WJ
The Journal of Neurophysiology 97:1196-1208, 2007

Recent Reviews and Book Chapters

"Evolution of the Study of Methylphenidate and its Actions on the Adult versus Juvenile Brain"
Kimberly R. Urban and Wen-Jun Gao
Journal of Attention Disorders (in press, 2012)

"The unique properties of the prefrontal cortex and mental illness"
Wen-Jun Gao*, Huai-Xing Wang, Melissa A. Snyder, and Yan-Chun Li
In When Things Go Wrong – Diseases and Disorders of the Human Brain, edited by Theo Mantamadiotis, Intech Publisher (2012)

"GSK-3 and hyperdopaminergic behaviors"
Yan-Chun Li and Wen-Jun Gao
Neuroscience & Biobehavioral Reviews. 35:645-654 (2011)

"Experimental strategies for investigating drug actions in ADHD and related attention disorders"
Agster K, Clark B, Gao WJ, Shumsky J, Wang HX, Berridge C and Waterhouse B
Anatomical Record, 294:1698-1712 (invited review, 2011)

"Dopaminergic and Glutamatergic Dysfunctions in the Neuropathophysiology of Schizophrenia"
Gao WJ
In Dopamine: Functions, Regulation and Health Effects, edited by Endo Kudo and Yuriko Fujii. Nova Publishers (2011)