@article{pmid41453484,

title = {Norepinephrine and inhibitory transmission: Regional diversity and mechanisms of modulation},

author = {Prabhjeet Singh and Tak Pan Wong},

doi = {10.1016/j.pnpbp.2025.111592},

issn = {1878-4216},

year  = {2026},

date = {2026-01-01},

journal = {Prog Neuropsychopharmacol Biol Psychiatry},

volume = {144},

pages = {111592},

abstract = {Norepinephrine, a stress-related neuromodulator, is a key regulator of synaptic transmission and neuronal activity. While the impact of norepinephrine on excitatory transmission has been frequently discussed, how norepinephrine regulates inhibitory transmission remains poorly understood. Norepinephrine modulates inhibitory synaptic function and the firing property of inhibitory neurons. These norepinephrine effects on inhibitory transmission are complex and often region- and inhibitory neuron subtype-specific. Malfunctioning of the norepinephrine-induced modulation of inhibitory transmission could underlie various brain diseases, especially norepinephrine-related psychiatric and neurodegenerative disorders. In this review, we examine findings on the expression of norepinephrine receptors in inhibitory neurons and norepinephrine-induced modulation of inhibitory transmission across different regions of the central nervous system. Furthermore, we discuss the role of adrenergic receptors, norepinephrine concentrations, signaling and inhibitory neuron subtypes in norepinephrine-induced modulation of inhibitory transmission. Overall, this review highlights inhibitory transmission as a major target of norepinephrine for influencing circuit functions and shaping behavioral outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41125449,

title = {Layer-Specific Glutamatergic Inputs and Parvalbumin Interneurons Modulate Early Life Stress-Induced Alterations in Prefrontal Glutamate Release during Fear Conditioning in Pre-adolescent Rats},

author = {Jiamin Song and Muzammil Younus and Hong Long and Tak Pan Wong and Claire-Dominique Walker},

doi = {10.1523/ENEURO.0073-25.2025},

issn = {2373-2822},

year  = {2025},

date = {2025-11-01},

journal = {eNeuro},

volume = {12},

number = {11},

abstract = {Exposure to early life stress (ELS) can exert long-lasting impacts on emotional regulation. The corticolimbic system including the basolateral amygdala (BLA), ventral hippocampus (vHIP), and the medial prefrontal cortex (mPFC) plays a key role in fear learning. Using the limited bedding paradigm (LB), we examined the functional consequences of ELS on excitatory and inhibitory tone in the prelimbic (PL) mPFC after fear conditioning in rats. In adults, LB exposure enhanced in vivo glutamate release in the PL mPFC during fear conditioning in male, but not female offspring. In contrast, the glutamate response to fear conditioning was diminished in LB-exposed pre-adolescent males, but not females. We investigated whether reduced glutamatergic inputs and/or elevated inhibitory tone might contribute to the diminished glutamate response in the mPFC following LB in pre-adolescent male rats. Indeed, we found that LB exposure specifically increased the activation of PV, but not SST interneurons in layer V, but not layer II/III of the PL mPFC in fear-exposed pre-adolescent males. Presynaptic glutamate release probability was reduced by LB exposure in layer V, but increased in layer II/III of the PL mPFC. These functional changes might be related to the LB-induced alterations in the bilaminar distribution of BLA and vHIP projections to the PL mPFC we observed in pre-adolescent males. Overall, our findings suggest that ELS modifies glutamate release and PL mPFC function during fear conditioning in a sex- and age-dependent fashion, likely through layer-specific shifts in excitation/inhibition balance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40115743,

title = {Diminished Social Memory and Hippocampal Correlates of Social Interactions in Chronic Social Defeat Stress Susceptibility},

author = {Amanda Larosa and Tian Rui Zhang and Alice S Wong and Cyrus Y H Fung and Xiong Ling Yun Jenny Long and Prabhjeet Singh and Benjamin C M Fung and Tak Pan Wong},

doi = {10.1016/j.bpsgos.2025.100455},

issn = {2667-1743},

year  = {2025},

date = {2025-05-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {5},

number = {3},

pages = {100455},

abstract = {BACKGROUND: Susceptibility to chronic stress has been associated with depression, a mood disorder that highly implicates the hippocampus. Hippocampal contribution to stress susceptibility has been supported by findings in mice following chronic social defeat stress (CSDS). However, little is known about the role of hippocampal activity in determining the development of stress susceptibility.nnMETHODS: We used the UCLA Miniscope to longitudinally measure the activity of dorsal CA1 hippocampal neurons during CSDS. In addition to examining the representation of social information by these neurons, we compared social memory in mice that were either susceptible or resilient to CSDS.nnRESULTS: We observed more stable dorsal CA1 correlates of social interaction and social memory in CSDS-resilient mice. Such changes were absent in CSDS-susceptible mice and accompanied by greater social memory impairments.nnCONCLUSIONS: CSDS susceptibility may be supported by hippocampal social cognitive processes, as reflected in diminished hippocampal representations of social information and greater impairment in social memory in suspectible compared with resilient mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39995200,

title = {Behavioral Tasks for Examining Identity Recognition In Mice},

author = {Amanda Larosa and Qi Wei Xu and Nastasia Maria Mitrikeski and Tak Pan Wong},

doi = {10.3791/67547},

issn = {1940-087X},

year  = {2025},

date = {2025-02-01},

journal = {J Vis Exp},

number = {216},

abstract = {Social animals, like rodents, are able to recognize and differentiate between the identity of familiar individuals. Recognizing the identity of familiar individuals is important for developing social structures such as hierarchy, kinship, and family. However, mechanisms underlying the recognition of social identity remain unclear. Most rodent studies of social recognition are based on the propensity of rodents to interact with a novel social target, a phenomenon known as social novelty. However, behavioral tasks for examining social novelty cannot reveal the recognition of familiar conspecifics based on their identities. Presented here are behavioral tasks allowing for the examination of identity recognition in C57BL/6 mice by associating two familiar mice with or without a valenced experience. Subjects had interactions with two mice either without (neutral) or with a valenced experience (negative or positive) and became familiar with these mice. The negatively valenced mouse was associated with shocks, while the positively valenced mouse was associated with a food reward. Following training, the recognition of the identity of these familiar mice can be revealed in a social discrimination test, which is represented as the preference for the positively valenced mouse and avoidance of the negatively valenced mouse compared to the neutral mouse. Behavioral tasks for identity recognition could be useful in probing social memory mechanisms and the pathophysiology of disorders with impaired social cognition, such as autism spectrum disorder or schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38956130,

title = {Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus},

author = {Sanjeev K Bhardwaj and Moushumi Nath and Tak Pan Wong and Lalit K Srivastava},

doi = {10.1038/s41598-024-65566-4},

issn = {2045-2322},

year  = {2024},

date = {2024-07-01},

journal = {Sci Rep},

volume = {14},

number = {1},

pages = {15239},

abstract = {Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39056071,

title = {Roles of AMPA receptors in social behaviors},

author = {Qi Wei Xu and Amanda Larosa and Tak Pan Wong},

doi = {10.3389/fnsyn.2024.1405510},

issn = {1663-3563},

year  = {2024},

date = {2024-01-01},

journal = {Front Synaptic Neurosci},

volume = {16},

pages = {1405510},

abstract = {As a crucial player in excitatory synaptic transmission, AMPA receptors (AMPARs) contribute to the formation, regulation, and expression of social behaviors. AMPAR modifications have been associated with naturalistic social behaviors, such as aggression, sociability, and social memory, but are also noted in brain diseases featuring impaired social behavior. Understanding the role of AMPARs in social behaviors is timely to reveal therapeutic targets for treating social impairment in disorders, such as autism spectrum disorder and schizophrenia. In this review, we will discuss the contribution of the molecular composition, function, and plasticity of AMPARs to social behaviors. The impact of targeting AMPARs in treating brain disorders will also be discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37432876,

title = { SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants},

author = {Rixing Lin and Aron Kos and Juan Pablo Lopez and Julien Dine and Laura M Fiori and Jennie Yang and Yair Ben-Efraim and Zahia Aouabed and Pascal Ibrahim and Haruka Mitsuhashi and Tak Pan Wong and El Cherif Ibrahim and Catherine Belzung and Pierre Blier and Faranak Farzan and Benicio N Frey and Raymond W Lam and Roumen Milev and Daniel J Muller and Sagar V Parikh and Claudio Soares and Rudolf Uher and Corina Nagy and Naguib Mechawar and Jane A Foster and Sidney H Kennedy and Alon Chen and Gustavo Turecki},

doi = {10.7554/eLife.85316},

issn = {2050-084X},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Elife},

volume = {12},

abstract = {Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, , was elevated following treatment response. When we increased  levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 () as one of the targets of , which we show is regulated through the accumulation of N-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36608782,

title = {Timely insertion of AMPA receptor in developing vestibular circuits is required for manifestation of righting reflexes and effective navigation},

author = {Suk-King Lai and Kenneth Lap Kei Wu and Chun-Wai Ma and Ka-Pak Ng and Xiao-Qian Hu and Kin-Wai Tam and Wing-Ho Yung and Yu Tian Wang and Tak Pan Wong and Daisy Kwok-Yan Shum and Ying-Shing Chan},

doi = {10.1016/j.pneurobio.2023.102402},

issn = {1873-5118},

year  = {2023},

date = {2023-02-01},

journal = {Prog Neurobiol},

volume = {221},

pages = {102402},

abstract = {Vestibular information processed first by the brainstem vestibular nucleus (VN), and further by cerebellum and thalamus, underlies diverse brain function. These include the righting reflexes and spatial cognitive behaviour. While the cerebellar and thalamic circuits that decode vestibular information are known, the importance of VN neurons and the temporal requirements for their maturation that allow developmental consolidation of the aforementioned circuits remains unclear. We show that timely unsilencing of glutamatergic circuits in the VN by NMDA receptor-mediated insertion of AMPAR receptor type 1 (GluA1) subunits is critical for maturation of VN and successful consolidation of higher circuits that process vestibular information. Delayed unsilencing of NMDA receptor-only synapses of neonatal VN neurons permanently decreased their functional connectivity with inferior olive circuits. This was accompanied by delayed pruning of the inferior olive inputs to Purkinje cells and permanent reduction in their plasticity. These derangements led to deficits in associated vestibular righting reflexes and motor co-ordination during voluntary movement. Vestibular-dependent recruitment of thalamic neurons was similarly reduced, resulting in permanently decreased efficiency of spatial navigation. The findings thus show that well-choreographed maturation of the nascent vestibular circuitry is prerequisite for functional integration of vestibular signals into ascending pathways for diverse vestibular-related behaviours.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35297476,

title = {Altered excitatory and decreased inhibitory transmission in the prefrontal cortex of male mice with early developmental disruption to the ventral hippocampus},

author = {Moushumi Nath and Sanjeev K Bhardwaj and Lalit K Srivastava and Tak Pan Wong},

doi = {10.1093/cercor/bhac107},

issn = {1460-2199},

year  = {2023},

date = {2023-01-01},

journal = {Cereb Cortex},

volume = {33},

number = {3},

pages = {865--880},

abstract = {Ventral hippocampal (vHPC)-prefrontal cortical (PFC) pathway dysfunction is a core neuroimaging feature of schizophrenia. However, mechanisms underlying impaired connectivity within this pathway remain poorly understood. The vHPC has direct projections to the PFC that help shape its maturation. Here, we wanted to investigate the effects of early developmental vHPC perturbations on long-term functional PFC organization. Using whole-cell recordings to assess PFC cellular activity in transgenic male mouse lines, we show early developmental disconnection of vHPC inputs, by excitotoxic lesion or cell-specific ablations, impairs pyramidal cell firing output and produces a persistent increase in excitatory and decrease in inhibitory synaptic inputs onto pyramidal cells. We show this effect is specific to excitatory vHPC projection cell ablation. We further identify PV-interneurons as a source of deficit in inhibitory transmission. We find PV-interneurons are reduced in density, show a reduced ability to sustain high-frequency firing, and show deficits in excitatory inputs that emerge over time. We additionally show differences in vulnerabilities to early developmental vHPC disconnection, wherein PFC PV-interneurons but not pyramidal cells show deficits in NMDA receptor-mediated current. Our results highlight mechanisms by which the PFC adapts to early developmental vHPC perturbations, providing insights into schizophrenia circuit pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37624765,

title = {Persistent extrasynaptic hyperdopaminergia in the mouse hippocampus induces plasticity and recognition memory deficits reversed by the atypical antipsychotic sulpiride},

author = {Jill Rocchetti and Caroline Fasano and Gregory Dal-Bo and Elisa Guma and Salah El Mestikawy and Tak-Pan Wong and Gohar Fakhfouri and Bruno Giros},

doi = {10.1371/journal.pone.0289770},

issn = {1932-6203},

year  = {2023},

date = {2023-01-01},

journal = {PLoS One},

volume = {18},

number = {8},

pages = {e0289770},

abstract = {Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35842073,

title = {The hippocampus in stress susceptibility and resilience: Reviewing molecular and functional markers},

author = {Amanda Larosa and Tak Pan Wong},

doi = {10.1016/j.pnpbp.2022.110601},

issn = {1878-4216},

year  = {2022},

date = {2022-12-01},

journal = {Prog Neuropsychopharmacol Biol Psychiatry},

volume = {119},

pages = {110601},

abstract = {Understanding the individual variability that comes with the likelihood of developing stress-related psychopathologies is of paramount importance when addressing mechanisms of their neurobiology. This article focuses on the hippocampus as a region that is highly influenced by chronic stress exposure and that has strong ties to the development of related disorders, such as depression and post-traumatic stress disorder. We first outline three commonly used animal models that have been used to separate animals into susceptible and resilient cohorts. Next, we review molecular and functional hippocampal markers of susceptibility and resilience. We propose that the hippocampus plays a crucial role in the differences in the processing and storage of stress-related information in animals with different stress susceptibilities. These hippocampal markers not only help us attain a more comprehensive understanding of the various facets of stress-related pathophysiology, but also could be targeted for the development of new treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32721441,

title = {Neurodevelopmental insights into circuit dysconnectivity in schizophrenia},

author = {Moushumi Nath and Tak Pan Wong and Lalit K Srivastava},

doi = {10.1016/j.pnpbp.2020.110047},

issn = {1878-4216},

year  = {2021},

date = {2021-01-01},

journal = {Prog Neuropsychopharmacol Biol Psychiatry},

volume = {104},

pages = {110047},

abstract = {Schizophrenia is increasingly being recognized as a disorder of brain circuits of developmental origin. Animal models, however, have been technically limited in exploring the effects of early developmental circuit abnormalities on the maturation of the brain and associated behavioural outputs. This review discusses evidence of the developmental emergence of circuit abnormalities in schizophrenia, followed by a critical assessment on how animal models need to be adapted through optimized tools in order to spatially and temporally manipulate early developmental events, thereby providing insight into the causal contribution of developmental perturbations to schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34690693,

title = {Opposing Changes in Synaptic and Extrasynaptic N-Methyl-D-Aspartate Receptor Function in Response to Acute and Chronic Restraint Stress},

author = {Yiu Chung Tse and Moushumi Nath and Amanda Larosa and Tak Pan Wong},

doi = {10.3389/fnmol.2021.716675},

issn = {1662-5099},

year  = {2021},

date = {2021-01-01},

journal = {Front Mol Neurosci},

volume = {14},

pages = {716675},

abstract = {A pertinent mechanism by which stress impacts learning and memory is through stress-induced plastic changes in glutamatergic transmission in the hippocampus. For instance, acute stress has been shown to alter the expression, binding, and function of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR). However, the consequences of chronic stress, which could lead to various stress-related brain disorders, on NMDAR function remain unclear. While most studies on NMDARs focused on these receptors in synapses (synaptic NMDARs or sNMDARs), emerging findings have revealed functional roles of NMDARs outside synapses (extrasynaptic NMDARs or exNMDARs) that are distinct from those of sNMDARs. Using a restraint stress paradigm in adult rats, the objective of the current study is to examine whether sNMDARs and exNMDARs in the hippocampus are differentially regulated by acute and chronic stress. We examined sNMDAR and exNMDAR function in dorsal CA1 hippocampal neurons from brain slices of adult rats that were acutely (1 episode) or chronically (21 daily episodes) stressed by restraint (30 min). We found that acute stress increases sNMDAR but suppresses exNMDAR function. Surprisingly, we only observed a reduction in exNMDAR function after chronic stress. Taken together, our findings suggest that sNMDARs and exNMDARs may be differentially regulated by acute and chronic stress. Most importantly, the observed suppression in exNMDAR function by both acute and chronic stress implies crucial but overlooked roles of hippocampal exNMDARs in stress-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32978287,

title = {It Is All in the Right Amygdala: Increased Synaptic Plasticity and Perineuronal Nets in Male, But Not Female, Juvenile Rat Pups after Exposure to Early-Life Stress},

author = {Angela Guadagno and Silvanna Verlezza and Hong Long and Tak Pan Wong and Claire-Dominique Walker},

doi = {10.1523/JNEUROSCI.1029-20.2020},

issn = {1529-2401},

year  = {2020},

date = {2020-10-01},

journal = {J Neurosci},

volume = {40},

number = {43},

pages = {8276--8291},

abstract = {Early-life stress (ELS) is associated with increased vulnerability to mental disorders. The basolateral amygdala (BLA) plays a critical role in fear conditioning and is extremely sensitive to ELS. Using a naturalistic rodent model of ELS, the limited bedding paradigm (LB) between postnatal days 1-10, we previously documented that LB male, but not female preweaning rat pups display increased BLA neuron spine density paralleled with enhanced evoked synaptic responses and altered BLA functional connectivity. Since ELS effects are often sexually dimorphic and amygdala processes exhibit hemispheric asymmetry, we investigated changes in synaptic plasticity and neuronal excitability of BLA neurons  in the left and right amygdala of postnatal days 22-28 male and female offspring from normal bedding or LB mothers. We report that LB conditions enhanced synaptic plasticity in the right, but not the left BLA of males exclusively. LB males also showed increased perineuronal net density, particularly around parvalbumin (PV) cells, and impaired fear-induced activity of PV interneurons only in the right BLA. Action potentials fired from right BLA neurons of LB females displayed slower maximal depolarization rates and decreased amplitudes compared with normal bedding females, concomitant with reduced NMDAR GluN1 subunit expression in the right BLA. In LB males, reduced GluA2 expression in the right BLA might contribute to the enhanced LTP. These findings suggest that LB differentially programs synaptic plasticity and PV/perineuronal net development in the left and right BLA. Furthermore, our study demonstrates that the effects of ELS exposure on BLA synaptic function are sexually dimorphic and possibly recruiting different mechanisms. Early-life stress (ELS) induces long-lasting consequences on stress responses and emotional regulation in humans, increasing vulnerability to the development of psychopathologies. The effects of ELS in a number of brain regions, including the amygdala, are often sexually dimorphic, and have been reproduced using the rodent limited bedding paradigm of early adversity. The present study examines sex differences in synaptic plasticity and cellular activation occurring in the developing left and right amygdala after limited bedding exposure, a phenomenon that could shape long-term emotional behavioral outcomes. Studying how ELS selectively produces effects in one amygdala hemisphere during a critical period of brain development could guide further investigation into sex-dependent mechanisms and allow for more targeted and improved treatment of stress-and emotionality-related disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31405928,

title = {Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress},

author = {Tian Rui Zhang and Amanda Larosa and Marie-Eve Di Raddo and Vanessa Wong and Alice S Wong and Tak Pan Wong},

doi = {10.1523/JNEUROSCI.1958-18.2019},

issn = {1529-2401},

year  = {2019},

date = {2019-09-01},

journal = {J Neurosci},

volume = {39},

number = {38},

pages = {7576--7590},

abstract = {The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor.  mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor. Compared with resilient and nonstressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e., engram cells) in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD and optogenetic approaches to activate and inactivate social defeat-related CA1 engram cells enhanced and suppressed social avoidance, respectively. Increased engram cells in susceptible mice could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-related, but not neutral stimuli-related, CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. The susceptibility to chronic social defeat stress is regulated by hippocampal CA1 engrams for negative memory. Hippocampal negative memory engrams may underlie the vulnerability and expression of cognitive symptoms in depression. We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams has been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31501443,

title = {p97 regulates GluA1 homomeric AMPA receptor formation and plasma membrane expression},

author = {Yuan Ge and Meng Tian and Lidong Liu and Tak Pan Wong and Bo Gong and Dongchuan Wu and Taesup Cho and Shujun Lin and Jürgen Kast and Jie Lu and Yu Tian Wang},

doi = {10.1038/s41467-019-12096-7},

issn = {2041-1723},

year  = {2019},

date = {2019-09-01},

journal = {Nat Commun},

volume = {10},

number = {1},

pages = {4089},

abstract = {The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity. In particular, the rapid insertion of the GluA1 homomeric (GluA1-homo) AMPARs into the postsynaptic membrane is considered to be critical in the expression of hippocampal CA1 long-term potentiation (LTP), which is important for certain forms of learning and memory. However, how the formation and trafficking of GluA1-homo AMPARs are regulated remains poorly understood. Here, we report that p97 specifically interacts with and promotes the formation of GluA1-homo AMPARs. The association with p97 retains GluA1-homo AMPARs in the intracellular compartment under basal conditions, and its dissociation allows GluA1-homo AMPARs to be rapidly inserted into the postsynaptic membrane shortly after LTP induction. Thus, our results shed lights into the molecular mechanisms by which p97 regulates GluA1-homo AMPARs formation and trafficking, thereby playing a critical role in mediating synaptic plasticity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30723288,

title = {The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function},

author = {Yiu Chung Tse and Joëlle Lopez and Alexandre Moquin and Shui-Ming Alice Wong and Dusica Maysinger and Tak Pan Wong},

doi = {10.1038/s41386-019-0325-8},

issn = {1740-634X},

year  = {2019},

date = {2019-06-01},

journal = {Neuropsychopharmacology},

volume = {44},

number = {7},

pages = {1310--1318},

abstract = {N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30679733,

title = {Heterochromatic genome instability and neurodegeneration sharing similarities with Alzheimer's disease in old Bmi1+/- mice},

author = {Jida El Hajjar and Wassim Chatoo and Roy Hanna and Patrick Nkanza and Nicolas Tétreault and Yiu Chung Tse and Tak Pan Wong and Mohamed Abdouh and Gilbert Bernier},

doi = {10.1038/s41598-018-37444-3},

issn = {2045-2322},

year  = {2019},

date = {2019-01-01},

journal = {Sci Rep},

volume = {9},

number = {1},

pages = {594},

abstract = {Sporadic Alzheimer's disease (AD) is the most common cause of dementia. However, representative experimental models of AD have remained difficult to produce because of the disease's uncertain origin. The Polycomb group protein BMI1 regulates chromatin compaction and gene silencing. BMI1 expression is abundant in adult brain neurons but down-regulated in AD brains. We show here that mice lacking one allele of Bmi1 (Bmi1+/-) develop normally but present with age cognitive deficits and neurodegeneration sharing similarities with AD. Bmi1+/- mice also transgenic for the amyloid beta precursor protein died prematurely and present aggravated disease. Loss of heterochromatin and DNA damage response (DDR) at repetitive DNA sequences were predominant in Bmi1+/- mouse neurons and inhibition of the DDR mitigated the amyloid and Tau phenotype. Heterochromatin anomalies and DDR at repetitive DNA sequences were also found in AD brains. Aging Bmi1+/- mice may thus represent an interesting model to identify and study novel pathogenic mechanisms related to AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}