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  1. Article: NMDAR modulators as rapid antidepressants: Converging and distinct signaling mechanisms.

    Lee, Boyoung / Pothula, Santosh / Duman, Ronald S

    Integrative clinical medicine

    2020  Volume 4, Issue 2

    Abstract: Dysregulation of the glutamatergic system underlies the pathophysiology of depression. Both negative and positive modulation of NMDARs exert rapid and sustained antidepressant effects by reversing the dysregulated glutamatergic system. Research in the ... ...

    Abstract Dysregulation of the glutamatergic system underlies the pathophysiology of depression. Both negative and positive modulation of NMDARs exert rapid and sustained antidepressant effects by reversing the dysregulated glutamatergic system. Research in the past decades has identified key signaling pathways activated by these rapid acting antidepressants. Here, we review the converging signaling mechanisms shared by rapid acting antidepressants and discuss the recent progress on distinct actions of NMDAR antagonists and NMDAR positive modulators to trigger rapid antidepressant actions.
    Language English
    Publishing date 2020-02-04
    Publishing country England
    Document type Journal Article
    ISSN 2515-0219
    ISSN 2515-0219
    DOI 10.15761/icm.1000173
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  2. Article ; Online: Stress and Its Impact on the Transcriptome.

    Girgenti, Matthew J / Pothula, Santosh / Newton, Samuel S

    Biological psychiatry

    2020  Volume 90, Issue 2, Page(s) 102–108

    Abstract: Exposure to stress during the course of a lifetime is inevitable in the animal kingdom. It is the response to stress, the valence of the exposure, and the developmental time point that largely determine the consequences to the initial and subsequent ... ...

    Abstract Exposure to stress during the course of a lifetime is inevitable in the animal kingdom. It is the response to stress, the valence of the exposure, and the developmental time point that largely determine the consequences to the initial and subsequent exposures. The versatility of transcriptomic methods to yield rich, high-resolution, information-laden datasets from entire brain regions to single cells makes it a powerful approach to investigate the effects of stress from several angles. Dysregulation of the transcriptome is now a phenotypic signature of many neuropsychiatric disorders. New insight has been gained from examining stress-induced changes in gene expression at a global scale. Human postmortem datasets from depression and posttraumatic stress disorder studies have identified major gene expression changes in the diseased brain, including sex-specific changes and marked differences in male and female molecular profiles for the same disorder. Extensions of this work into animal models have explored the impact of transcriptomic dysregulation on early-life stress, chronic stress, and transgenerational impact of stress. Here, we explore the findings of human postmortem genomic studies of neuropsychiatric disorders and comparable animal models through the lens of transcriptomic dysregulation and how these findings have contributed to our understanding of stress.
    MeSH term(s) Animals ; Brain ; Female ; Humans ; Male ; Stress Disorders, Post-Traumatic ; Stress, Psychological/genetics ; Transcriptome
    Language English
    Publishing date 2020-12-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2020.12.011
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  3. Article ; Online: Ketamine increases vmPFC activity: Effects of (R)- and (S)-stereoisomers and (2R,6R)-hydroxynorketamine metabolite.

    Hare, Brendan D / Pothula, Santosh / DiLeone, Ralph J / Duman, Ronald S

    Neuropharmacology

    2020  Volume 166, Page(s) 107947

    Abstract: Ketamine, an NMDA receptor antagonist and fast acting antidepressant, produces a rapid burst of glutamate in the ventral medial prefrontal cortex (mPFC). Preclinical studies have demonstrated that pyramidal cell activity in the vmPFC is necessary for the ...

    Abstract Ketamine, an NMDA receptor antagonist and fast acting antidepressant, produces a rapid burst of glutamate in the ventral medial prefrontal cortex (mPFC). Preclinical studies have demonstrated that pyramidal cell activity in the vmPFC is necessary for the rapid antidepressant response to ketamine in rodents. We sought to characterize the effects of ketamine and its stereoisomers (R and S), as well as a metabolite, (2R,6R)-hydroxynorketamine (HNK), on vmPFC activity using a genetically encoded calcium indicator (GCaMP6f). Ratiometric fiber photometry was utilized to monitor GCaMP6f fluorescence in pyramidal cells of mouse vmPFC prior to and immediately following administration of compounds. GCaMP6f signal was assessed to determine correspondance of activity between compounds. We observed dose dependent effects with (R,S)-ketamine (3-100 mg/kg), with the greatest effects on GCaMP6f activity at 30 mg/kg and lasting up to 20 min. (S)-ketamine (15 mg/kg), which has high affinity for the NMDA receptor channel produced similar effects to (R,S)-ketamine, but compounds with low NMDA receptor affinity, including (R)-ketamine (15 mg/kg) and (2R,6R)-HNK (30 mg/kg) had little or no effect on GCaMP6f activity. The initial response to administration of (R,S)-ketamine as well as (S)-ketamine is characterized by a brief period of robust GCaMP6f activation, consistent with increased activity of vmPFC pyramidal neurons. Because (2R,6R)-HNK and (R)-ketamine are reported to have antidepressant activity in rodent models the current results indicate that different initiating mechanisms lead to similar brain adaptive consequences that underlie the rapid antidepressant responses.
    MeSH term(s) Animals ; Dose-Response Relationship, Drug ; Excitatory Amino Acid Antagonists/chemistry ; Excitatory Amino Acid Antagonists/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Ketamine/analogs & derivatives ; Ketamine/chemistry ; Ketamine/metabolism ; Ketamine/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Photometry/methods ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/metabolism ; Stereoisomerism
    Chemical Substances Excitatory Amino Acid Antagonists ; Ketamine (690G0D6V8H) ; 6-hydroxynorketamine (81395-70-2)
    Language English
    Publishing date 2020-01-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2020.107947
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  4. Article ; Online: Author Correction: Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines.

    Ali, Farhan / Gerhard, Danielle M / Sweasy, Katherine / Pothula, Santosh / Pittenger, Christopher / Duman, Ronald S / Kwan, Alex C

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 370

    Language English
    Publishing date 2021-01-08
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-20634-x
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  5. Article ; Online: Positive modulation of N-methyl-D-aspartate receptors in the mPFC reduces the spontaneous recovery of fear.

    Lee, Boyoung / Pothula, Santosh / Wu, Min / Kang, Hyeyeon / Girgenti, Matthew J / Picciotto, Marina R / DiLeone, Ralph J / Taylor, Jane R / Duman, Ronald S

    Molecular psychiatry

    2022  Volume 27, Issue 5, Page(s) 2580–2589

    Abstract: N-methyl-D-aspartate receptor (NMDAR) modulators have recently received increased attention as potential therapeutics for posttraumatic stress disorder (PTSD). Here, we tested a novel NMDAR-positive modulator, NYX-783, in the following two rodent models ... ...

    Abstract N-methyl-D-aspartate receptor (NMDAR) modulators have recently received increased attention as potential therapeutics for posttraumatic stress disorder (PTSD). Here, we tested a novel NMDAR-positive modulator, NYX-783, in the following two rodent models of PTSD: an auditory fear-conditioning model and a single-prolonged stress (SPS) model. We examined the ability of NYX-783 to reduce subsequent fear-based behaviors by measuring enhanced fear extinction and reduced spontaneous recovery (spontaneous return of fear) in male mice. NYX-783 administration significantly reduced spontaneous recovery in both PTSD models and enhanced fear extinction in the SPS model. Furthermore, NYX-783 increased the NMDA-induced inward currents of excitatory and inhibitory neurons in the infralimbic medial prefrontal cortex (IL mPFC) and that the GluN2B subunit of NMDARs on pyramidal neurons in the IL mPFC is required for its effect on spontaneous recovery. The downstream expression of brain-derived neurotrophic factor was required for NYX-783 to achieve its behavioral effect. These results elucidate the cellular targets of NYX-783 and the molecular mechanisms underlying the inhibition of spontaneous recovery. These preclinical findings support the hypothesis that NYX-783 may have therapeutic potential for PTSD treatment and may be particularly useful for inhibiting spontaneous recovery.
    MeSH term(s) Animals ; Extinction, Psychological/physiology ; Fear/physiology ; Male ; Mice ; Prefrontal Cortex/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism
    Chemical Substances Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2022-04-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-022-01498-7
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  6. Article ; Online: Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [

    Asch, Ruth H / Pothula, Santosh / Toyonaga, Takuya / Fowles, Krista / Groman, Stephanie M / Garcia-Milian, Rolando / DiLeone, Ralph J / Taylor, Jane R / Esterlis, Irina

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2022  Volume 48, Issue 3, Page(s) 489–497

    Abstract: Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron ... ...

    Abstract Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron emission tomography (PET) to examine the relationship between mGluR5 availability and differences in the response of rats to repeated footshock exposure (FE). Specifically, on day 1, male (n = 16) and female (n = 12) rats received 15 footshocks and were compared with control rats who did not receive footshocks (n = 7 male; n = 4 female). FE rats were classified as low responders (LR) or high responders (HR) based on freezing to the context the following day (day 2). PET with [
    MeSH term(s) Animals ; Female ; Male ; Rats ; Positron-Emission Tomography/methods ; Receptor, Metabotropic Glutamate 5/metabolism ; Sex Factors
    Chemical Substances Receptor, Metabotropic Glutamate 5
    Language English
    Publishing date 2022-09-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-022-01441-y
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  7. Article ; Online: Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines.

    Ali, Farhan / Gerhard, Danielle M / Sweasy, Katherine / Pothula, Santosh / Pittenger, Christopher / Duman, Ronald S / Kwan, Alex C

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 72

    Abstract: A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act ... ...

    Abstract A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine's actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.
    MeSH term(s) Animals ; Calcium/metabolism ; Dendritic Spines/drug effects ; Dendritic Spines/genetics ; Dendritic Spines/metabolism ; Interneurons/drug effects ; Interneurons/metabolism ; Ketamine/administration & dosage ; Male ; Mice ; Mice, Inbred C57BL ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/metabolism ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism
    Chemical Substances Receptors, N-Methyl-D-Aspartate ; Ketamine (690G0D6V8H) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2020-01-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-13809-8
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  8. Article ; Online: Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation.

    Ali, Farhan / Shao, Ling-Xiao / Gerhard, Danielle M / Sweasy, Katherine / Pothula, Santosh / Pittenger, Christopher / Duman, Ronald S / Kwan, Alex C

    Molecular psychiatry

    2020  Volume 26, Issue 6, Page(s) 1945–1966

    Abstract: The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the ... ...

    Abstract The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.
    MeSH term(s) Animals ; Autism Spectrum Disorder ; Calcium ; Codon, Nonsense ; Dendritic Spines ; Mice ; Microfilament Proteins ; Nerve Tissue Proteins/genetics ; Synapses
    Chemical Substances Codon, Nonsense ; Microfilament Proteins ; Nerve Tissue Proteins ; Shank3 protein, mouse ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2020-03-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-020-0708-6
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  9. Article ; Online: Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons.

    Pothula, Santosh / Liu, Rong-Jian / Wu, Min / Sliby, Alexa-Nicole / Picciotto, Marina R / Banerjee, Pradeep / Duman, Ronald S

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2020  Volume 46, Issue 4, Page(s) 799–808

    Abstract: Dysregulation of the glutamatergic system and its receptors in medial prefrontal cortex (mPFC) has been implicated in major depressive disorder. Recent preclinical studies have shown that enhancing NMDA receptor (NMDAR) activity can exert rapid ... ...

    Abstract Dysregulation of the glutamatergic system and its receptors in medial prefrontal cortex (mPFC) has been implicated in major depressive disorder. Recent preclinical studies have shown that enhancing NMDA receptor (NMDAR) activity can exert rapid antidepressant-like effects. AGN-241751, an NMDAR positive allosteric modulator (PAM), is currently being tested as an antidepressant in clinical trials, but the mechanism and NMDAR subunit(s) mediating its antidepressant-like effects are unknown. We therefore used molecular, biochemical, and electrophysiological approaches to examine the cell-type-specific role of GluN2B-containing NMDAR in mediating antidepressant-like behavioral effects of AGN-241751. We demonstrate that AGN-241751 exerts antidepressant-like effects and reverses behavioral deficits induced by chronic unpredictable stress in mice. AGN-241751 treatment enhances NMDAR activity of excitatory and parvalbumin-inhibitory neurons in mPFC, activates Akt/mTOR signaling, and increases levels of synaptic proteins crucial for synaptic plasticity in the prefrontal cortex. Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects.
    MeSH term(s) Animals ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Depressive Disorder, Major/drug therapy ; Mice ; Neurons/metabolism ; Prefrontal Cortex/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism
    Chemical Substances Antidepressive Agents ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2020-10-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-020-00882-7
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  10. Article ; Online: Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation.

    Kato, Taro / Pothula, Santosh / Liu, Rong-Jian / Duman, Catharine H / Terwilliger, Rosemarie / Vlasuk, George P / Saiah, Eddine / Hahm, Seung / Duman, Ronald S

    The Journal of clinical investigation

    2019  Volume 129, Issue 6, Page(s) 2542–2554

    Abstract: Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which ... ...

    Abstract Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.
    MeSH term(s) Animals ; Antidepressive Agents/chemistry ; Antidepressive Agents/pharmacokinetics ; Antidepressive Agents/pharmacology ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/genetics ; Brain-Derived Neurotrophic Factor/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Male ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Mice, Knockout ; Rats ; Rats, Sprague-Dawley ; Synaptic Transmission/drug effects ; Synaptic Transmission/genetics
    Chemical Substances Antidepressive Agents ; Bdnf protein, mouse ; Bdnf protein, rat ; Brain-Derived Neurotrophic Factor ; Heat-Shock Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
    Language English
    Publishing date 2019-04-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI126859
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