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1.
Biochem Biophys Res Commun ; 637: 100-107, 2022 12 31.
Article in English | MEDLINE | ID: mdl-36395691

ABSTRACT

Recently, we reported that auditory fear conditioning leads to the presynaptic potentiation at lateral amygdala to basal amygdala (LA-BA) synapses that shares the mechanism with high-frequency stimulation (HFS)-induced long-term potentiation (LTP) ex vivo. In the present study, we further examined the molecular mechanisms underlying the HFS-induced presynaptic LTP. We found that a presynaptic elevation of Ca2+ was required for the LTP induction. Interestingly, the blockade of presynaptic but not postsynaptic HCN channels with ZD7288 completely abolished LTP induction. While ZD7288 did not alter basal synaptic transmission, the blocker fully reversed previously established LTP, indicating that HCN channels are also required for the maintenance of LTP. Indeed, HCN3 and HCN4 channels were preferentially localized in the presynaptic boutons of LA afferents. Furthermore, an inhibition of either GABAB receptors or GIRK channels eliminated the inhibitory effect of HCN blockade on the LTP induction. Collectively, we suggest that activation of presynaptic HCN channels may counteract membrane hyperpolarization during tetanic stimulation, and thereby contributes to the presynaptic LTP at LA-BA synapses.


Subject(s)
Basolateral Nuclear Complex , Long-Term Potentiation , Synapses , Synaptic Transmission , Presynaptic Terminals
2.
Biochem Biophys Res Commun ; 627: 97-102, 2022 10 30.
Article in English | MEDLINE | ID: mdl-36030658

ABSTRACT

A nuclear serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a critical regulator of development and DNA damage response. HIPK2 can induce apoptosis under cellular stress conditions and thus its protein level is maintained low by constant proteasomal degradation. In the present study, we present evidence that TNF receptor-associated factor 2 (TRAF2) regulates the protein stability of HIPK2. Overexpression of TRAF2 decreased while its knockdown increased the HIPK2 protein level. The TRAF2-mediated decrease in HIPK2 protein expression was blocked by proteasomal inhibitor. In addition, TRAF2 decreased the protein half-life of HIPK2. We found that HIPK2 and TRAF2 co-immunoprecipitated. Interestingly, the co-immunoprecipitation was reduced while HIPK2 protein level increased following TNFα treatment, suggesting TNFα induced dissociation of TRAF2 from HIPK2 to accumulate HIPK2. Inhibition of HIPK2 partially suppressed TNFα-induced cell death, indicating that the accumulated HIPK2 may contribute to the TNFα-induced cell death. Our results suggest that TRAF2 can regulate proapoptotic function of HIPK2 by promoting proteasomal degradation.


Subject(s)
Protein Serine-Threonine Kinases , Tumor Necrosis Factor-alpha , Apoptosis , Protein Serine-Threonine Kinases/genetics , Protein Stability , TNF Receptor-Associated Factor 2/metabolism , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Ubiquitin-Protein Ligases/metabolism
3.
Biochem Biophys Res Commun ; 584: 39-45, 2021 12 20.
Article in English | MEDLINE | ID: mdl-34768080

ABSTRACT

The lateral amygdala (LA) is a main sensory input site from the cortical and thalamic regions. In turn, LA glutamatergic pyramidal neurons strongly project to the basal amygdala (BA). Although it is well known that auditory fear conditioning involves synaptic potentiation in the LA, it is not clear whether the LA-BA synaptic transmission is modified upon auditory fear conditioning. Here we found that high-frequency stimulation ex vivo resulted in long-term potentiation (LTP) with a concomitant enhancement of neurotransmitter release at LA-BA synapses. Auditory fear conditioning also led to the presynaptic facilitation at LA-BA synapses. Meanwhile, AMPA/NMDA current ratio was not changed upon fear conditioning, excluding the involvement of postsynaptic mechanism. Notably, fear conditioning occluded electrically induced ex vivo LTP in the LA-BA pathway, indicating that the conditioning and electrically induced LTP share common mechanisms. Our findings suggest that the presynaptic potentiation of LA-BA synapses may be involved in fear conditioning.


Subject(s)
Basolateral Nuclear Complex/physiology , Conditioning, Classical/physiology , Fear/physiology , Neurotransmitter Agents/metabolism , Synapses/physiology , Acoustic Stimulation , Amygdala/metabolism , Amygdala/physiology , Animals , Basolateral Nuclear Complex/cytology , Basolateral Nuclear Complex/metabolism , Long-Term Potentiation/physiology , Male , Neurons/cytology , Neurons/metabolism , Neurons/physiology , Rats, Sprague-Dawley , Receptors, AMPA/metabolism , Receptors, AMPA/physiology , Synapses/metabolism , Synaptic Transmission/physiology
4.
Biochem Biophys Res Commun ; 526(4): 986-992, 2020 06 11.
Article in English | MEDLINE | ID: mdl-32295715

ABSTRACT

PARP-1 is a multifunctional enzyme that regulates DNA repair, chromatin remodeling, inflammation and cell survival. Our previous study revealed that PARP-1 is required for maintaining normal level of neural stem cell proliferation. In the present study, we present evidence indicating that PARP-1 regulates neural stem cell proliferation by upregulating the expression of platelet-derived growth factor receptor α (PDGFRα). PARP-1 knockout neural stem cells exhibited striking downregulation of PDGFRα expression. We found that PARP-1 promotes the transcription of PDGFRα independently of its enzymatic activity. Overexpression of PDGFRα in the PARP-1 knockout neural stem cells reversed the proliferation defect of the knockout cells. Conversely, knockdown or blocking antibody of PDGFRα suppressed the proliferation of neural stem cells. In addition, blockade of PDGFRα increased cell death rate. Consistent with the downregulation of PDGFRα in the absence of PARP-1, PDGF-AA promoted proliferation of wild-type neural stem cells but not that of PARP-1 knockout cells. These results suggest that PARP-1 can control the neural stem cell proliferation by regulating the expression of PDGFRα.


Subject(s)
Mouse Embryonic Stem Cells/cytology , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Animals , Cell Proliferation , Cell Survival , Down-Regulation/genetics , Ligands , Mice , Mice, Inbred C57BL
5.
Cell Death Dis ; 10(12): 943, 2019 12 09.
Article in English | MEDLINE | ID: mdl-31819047

ABSTRACT

In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.


Subject(s)
Behavior, Animal , Neurogenesis/genetics , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Schizophrenia/metabolism , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Hippocampus/metabolism , Male , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Knockout , Mouse Embryonic Stem Cells/metabolism , Neural Stem Cells/metabolism , Transfection
6.
Biochem Biophys Res Commun ; 515(3): 468-473, 2019 07 30.
Article in English | MEDLINE | ID: mdl-31167722

ABSTRACT

The ventral subiculum (vSub) is the major output structure of the hippocampus and serves as a main limbic region in mediating the brain's response to stress. Previously, we reported that there are three subtypes of vSub neurons based on their firing patterns: regular-spiking (RS), weak-bursting (WB) and strong-bursting (SB) neurons and chronic social defeat stress (CSDS) increased SB neurons especially in the proximal vSub. Here, we found that neurons in the proximal vSub projected to the nucleus accumbens (NAc). CSDS significantly increased SB neurons but decreased RS neurons among the NAc-projecting vSub neuronal population. Interestingly, these changes were only apparent in mice susceptible to CSDS, but not in CSDS-resilient ones. Given that ventral hippocampal inputs to the NAc regulate susceptibility to CSDS, the bursting activity of NAc-projecting vSub neurons might be functionally relevant to behavioral susceptibility to CSDS.


Subject(s)
Action Potentials , Neurons/pathology , Nucleus Accumbens/physiopathology , Social Behavior , Stress, Psychological/physiopathology , Animals , Avoidance Learning , Disease Susceptibility , Interpersonal Relations , Male , Mice, Inbred C57BL
7.
Biochem Biophys Res Commun ; 508(4): 1182-1187, 2019 01 22.
Article in English | MEDLINE | ID: mdl-30554654

ABSTRACT

The ventral subiculum (vSub), a representative output structure of the hippocampus, serves as a main limbic region in mediating the brain's response to stress. There are three subtypes of subicular pyramidal neurons based on their firing patterns: regular-spiking (RS), weak-bursting (WB) and strong-bursting (SB) neurons, located differently along proximal-distal axis. Here, we found that chronic social defeat stress (CSDS) in mice increased the population of SB neurons but decreased RS neurons in the proximal vSub. Specific blockers of T-type calcium channels inhibited the burst firings with a concomitant reduction of afterdepolarization, suggesting that T-type calcium channels underlie the burst-spiking activity. Consistently, CSDS increased both T-type calcium currents and expression of Cav3.1 proteins, a subtype of T-type calcium channels, in the proximal vSub. Therefore, we conclude that CSDS-induced enhancement of Cav3.1 expression increased bursting neuronal population in the vSub, which may contribute to stress-related behaviors.


Subject(s)
Action Potentials/physiology , Calcium Channels, T-Type/metabolism , Hippocampus/physiopathology , Neurons/physiology , Social Behavior , Stress, Psychological/metabolism , Stress, Psychological/physiopathology , Action Potentials/drug effects , Animals , Calcium Channel Blockers/pharmacology , Chronic Disease , Hippocampus/drug effects , Male , Mice, Inbred C57BL , Neurons/drug effects
8.
Anim Cells Syst (Seoul) ; 22(3): 165-171, 2018.
Article in English | MEDLINE | ID: mdl-30460094

ABSTRACT

The medial habenula (MHb) plays an important role in nicotine-related behaviors, such as aversion and withdrawal. The MHb is composed of distinct subregions with unique neurotransmitter expression and neuronal connectivity. Here, we showed that nicotine and substance P (SP) differentially regulate neuronal excitability in subdivisions of the MHb (ventrolateral division, MHbVL; dorsal division; MHbD and superior division: MHbS). Nicotine remarkably increased spontaneous neuronal firing in the MHbVL and MHbD, but not in the MHbS, which was consistent with different magnitudes of whole-cell inward currents evoked by nicotine in each subdivision. Meanwhile, SP enhanced neuronal excitability in the MHbVL and MHbS. Although the MHbD is composed of SP-expressing neurons, they did not respond to SP. Neurons in the MHbVL increased their firing in response to bath-applied nicotine, which was attenuated by neurokinin receptor antagonists. Furthermore, nicotine addiction and withdrawal attenuated and augmented excitatory SP effects in the MHbVL, respectively. On the whole, we suggest that MHb-involving nicotine-related behaviors might be associated with SP signaling in MHb subdivisions.

9.
Sci Rep ; 7(1): 16136, 2017 11 23.
Article in English | MEDLINE | ID: mdl-29170424

ABSTRACT

Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase that functions in development and tumor suppression. One of the prominent features of this kinase is that it is tightly regulated by proteasomal degradation. In the present study, we present evidence suggesting that the protein stability of HIPK2 can be regulated by p300-mediated acetylation. p300 increased the protein level of HIPK2 via its acetyltransferase activity. p300 increased the acetylation of HIPK2 while decreased polyubiquitination and its proteasomal degradation. We also observed that DNA damage induced acetylation of HIPK2 along with an increase in the protein amount, which was inhibited by p300 RNAi. Importantly, p300 promoted p53 activation and the HIPK2-mediated suppression of cell proliferation, suggesting acetylation-induced HIPK2 stabilization contributed to the enhanced activation of HIPK2. Overexpression of p300 promoted the HIPK2-mediated suppression of tumor growth in mouse xenograft model as well. Taken together, our data suggest that p300-mediated acetylation of HIPK2 increases the protein stability of HIPK2 and enhances its tumor suppressor function.


Subject(s)
Carrier Proteins/metabolism , Cell Survival/physiology , E1A-Associated p300 Protein/metabolism , Protein Serine-Threonine Kinases/metabolism , Acetylation , Animals , Blotting, Western , Carrier Proteins/genetics , Cell Survival/genetics , E1A-Associated p300 Protein/genetics , HEK293 Cells , Humans , Immunoprecipitation , Mice , Mice, Inbred BALB C , Protein Serine-Threonine Kinases/genetics , Protein Stability , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
10.
Am J Cancer Res ; 7(3): 518-530, 2017.
Article in English | MEDLINE | ID: mdl-28401008

ABSTRACT

Autophagy is a cellular process by which damaged organelles and dysfunctional proteins are degraded. Morusin is an anti-cancer drug isolated from the root bark of Morus alba. Morusin induces apoptosis in human prostate cancer cells by reducing STAT3 activity. In this study, we examined whether morusin induces autophagy and also examined the effects of autophagy on the morusin-induced apoptosis. Morusin induces LC3-II accumulation and ULK1 activation in HeLa cells. In addition, we found that induction of ULK1 Ser317 phosphorylation and reduction of ULK1 Ser757 phosphorylation occurred simultaneously during morusin-induced autophagy. Consistently, morusin induces autophagy by activation of AMPK and inhibition of mTOR activity. Next, we investigated the role of autophagy in morusin-induced apoptosis. Inhibition of autophagy by treating cells with the 3-methyladenine (3-MA) autophagic inhibitor induces high levels of morusin-mediated apoptosis, while treatment of cells with morusin alone induces moderate levels of apoptosis. Cell survival was greatly reduced when cells were treated with morusin and 3-MA. Taken together, morusin induces autophagy, which is an impediment for morusin-induced apoptosis, suggesting combined treatment of morusin with an autophagic inhibitor would increase the efficacy of morusin as an anti-cancer drug.

11.
Sci Rep ; 6: 34800, 2016 10 05.
Article in English | MEDLINE | ID: mdl-27703268

ABSTRACT

The medial habenula (MHb) plays an important role in nicotine-related behaviors such as nicotine aversion and withdrawal. The MHb receives GABAergic input from the medial septum/diagonal band of Broca (MS/DB), yet the synaptic mechanism that regulates MHb activity is unclear. GABA (γ -aminobutyric acid) is a major inhibitory neurotransmitter activating both GABAA receptors and GABAB receptors. Depending on intracellular chloride concentration, however, GABAA receptors also function in an excitatory manner. In the absence of various synaptic inputs, we found that MHb neurons displayed spontaneous tonic firing at a rate of about ~4.4 Hz. Optogenetic stimulation of MS/DB inputs to the MHb evoked GABAA receptor-mediated synaptic currents, which produced stimulus-locked neuronal firing. Subsequent delayed yet lasting activation of GABAB receptors attenuated the intrinsic tonic firing. Consequently, septal GABAergic input alone orchestrates both excitatory GABAA and inhibitory GABAB receptors, thereby entraining the firing of MHb neurons.


Subject(s)
Habenula/physiology , Neurons/physiology , Optogenetics/methods , Receptors, GABA-A/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Male , Mice , Synaptic Transmission
12.
Cell Death Dis ; 7(10): e2438, 2016 10 27.
Article in English | MEDLINE | ID: mdl-27787517

ABSTRACT

Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase that functions in DNA damage response and development. In the present study, we propose that the protein stability and proapoptotic function of HIPK2 are regulated by poly(ADP-ribose) polymerase 1 (PARP1). We present evidence indicating that PARP1 promotes the proteasomal degradation of HIPK2. The tryptophan-glycine-arginine (WGR) domain of PARP1 was necessary and sufficient for the promotion of HIPK2 degradation independently of the PARP1 enzymatic activity. The WGR domain mediated the interaction between HIPK2 and C-terminus of HSP70-interacting protein (CHIP) via HSP70. We found that CHIP can function as a ubiquitin ligase for HIPK2. The interaction between PAPR1 and HIPK2 was weakened following DNA damage. Importantly, PARP1 reduced the HIPK2-mediated p53 phosphorylation, proapoptotic transcriptional activity and cell death. These results suggest that PARP1 can modulate the tumor-suppressing function of HIPK2 by regulating the protein stability of HIPK2.


Subject(s)
Apoptosis , Carrier Proteins/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Protein Serine-Threonine Kinases/metabolism , DNA Damage , HCT116 Cells , HEK293 Cells , HSP70 Heat-Shock Proteins/metabolism , Humans , Poly(ADP-ribose) Polymerases/chemistry , Protein Binding , Protein Interaction Domains and Motifs , Protein Stability , Proteolysis , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/metabolism
13.
Sci Rep ; 5: 17796, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26634434

ABSTRACT

Neuronal loss caused by neurodegenerative diseases, traumatic brain injury and stroke results in cognitive dysfunctioning. Implantation of neural stem/precursor cells (NPCs) can improve the brain function by replacing lost neurons. Proper synaptic integration following neuronal differentiation of implanted cells is believed to be a prerequisite for the functional recovery. In the present study, we characterized the functional properties of immortalized neural progenitor HiB5 cells implanted into the rat hippocampus with chemically induced lesion. The implanted HiB5 cells migrated toward CA1 pyramidal layer and differentiated into vGluT1-positive glutamatergic neurons with morphological and electrophysiological properties of endogenous CA1 pyramidal cells. Functional synaptic integration of HiB5 cell-derived neurons was also evidenced by immunohistochemical and electrophysiological data. Lesion-caused memory deficit was significantly recovered after the implantation when assessed by inhibitory avoidance (IA) learning. Remarkably, IA learning preferentially produced long-term potentiation (LTP) at the synapses onto HiB5 cell-derived neurons, which occluded paring protocol-induced LTP ex vivo. We conclude that the implanted HiB5 cell-derived neurons actively participate in learning process through LTP formation, thereby counteracting lesion-mediated memory impairment.


Subject(s)
Cell Differentiation , Cognition Disorders/therapy , Neural Stem Cells/transplantation , Neurons/metabolism , Animals , CA1 Region, Hippocampal/growth & development , CA1 Region, Hippocampal/physiopathology , Cognition Disorders/physiopathology , Hippocampus/growth & development , Hippocampus/physiopathology , Humans , Learning/physiology , Neural Stem Cells/physiology , Neurons/pathology , Rats , Synapses/physiology
14.
Mol Cells ; 38(8): 734-40, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26242194

ABSTRACT

Recent studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinson's disease (PD). However, it remains unclear whether antidepressant use can be a causative factor for PD. In the present study, we examined whether tricyclic antidepressants amitriptyline and desipramine can induce dopaminergic cell damage, both in vitro and in vivo. We found that amitriptyline and desipramine induced mitochondria-mediated neurotoxicity and oxidative stress in SH-SY5Y cells. When injected into mice on a subchronic schedule, amitriptyline induced movement deficits in the pole test, which is known to detect nigrostriatal dysfunction. In addition, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was reduced in amitriptyline-injected mice. Our results suggest that amitriptyline and desipramine may induce PD-associated neurotoxicity.


Subject(s)
Amitriptyline/pharmacology , Antidepressive Agents, Tricyclic/pharmacology , Desipramine/pharmacology , Dopaminergic Neurons/drug effects , Parkinson Disease/metabolism , Adenosine Triphosphate/metabolism , Amitriptyline/toxicity , Animals , Antioxidants/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Desipramine/toxicity , Humans , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Reactive Oxygen Species/metabolism
15.
Emerg Infect Dis ; 21(7): 1247-50, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26079171

ABSTRACT

We investigated an October 2014 outbreak of illness caused by Shigella sonnei in a daycare center in the Republic of Korea (South Korea). The outbreak strain was resistant to extended-spectrum cephalosporins and fluoroquinolones and was traced to a child who had traveled to Vietnam. Improved hygiene and infection control practices are needed for prevention of shigellosis.


Subject(s)
Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Disease Outbreaks , Dysentery, Bacillary/drug therapy , Shigella sonnei/drug effects , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Ciprofloxacin/therapeutic use , Drug Resistance, Multiple, Bacterial , Dysentery, Bacillary/epidemiology , Dysentery, Bacillary/microbiology , Female , Genes, Bacterial , Humans , Male , Republic of Korea/epidemiology , Travel , Vietnam , beta-Lactam Resistance
16.
Cardiovasc Toxicol ; 15(2): 197-202, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25253561

ABSTRACT

Some non-antiarrhythmic drugs have the undesirable property of delaying cardiac repolarization, an effect that can be measured empirically as a prolongation of the QT interval by surface electrocardiogram (ECG). The QT prolongation and proarrhythmia potential of famotidine are largely unknown, particularly in individuals that have cardiovascular risk factors such as abnormal electrolyte levels. Based on an analysis of QT/QTc intervals from a database of ECG recordings from a large Korean population (ECG-ViEW, 710,369 ECG recordings from 371,401 individuals), we observed that famotidine administration induced a prolonged QTc interval (above 480 ms, p < 0.05 compared to before-treatment, based on a McNemar test). Furthermore, famotidine induced QT prolongations in 10 out of 14 patients with hypocalcemia and 11 out of 13 patients with hypomagnesemia [difference of mean between before and after famotidine administration; 38.00 ms (95% confidence interval 2.72-73.28) and 67.08 ms (95% confidence interval 24.94-109.21), p < 0.05 and p < 0.01 by paired t test, respectively]. In vitro, the IC50 of famotidine for human-ether-a-go-go gene (hERG) channel inhibition was higher than 100 µM as determined by automated patch clamp hERG current assay, implying that hERG channel inhibition is not the underlying mechanism for QT prolongation. These results suggest that famotidine administration increases a proarrhythmic potential, especially in subjects with electrolytes imbalance.


Subject(s)
Databases, Factual , Electrocardiography/drug effects , Famotidine/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Population Surveillance , Anti-Ulcer Agents/adverse effects , Databases, Factual/trends , Electrocardiography/trends , Female , HEK293 Cells , Humans , Long QT Syndrome/diagnosis , Male , Republic of Korea/epidemiology
17.
BMC Neurosci ; 15: 65, 2014 May 22.
Article in English | MEDLINE | ID: mdl-24884833

ABSTRACT

BACKGROUND: Glucocorticoid released by stressful stimuli elicits various stress responses. Acute treatment with a single dose of corticosterone (CORT; predominant glucocorticoid of rats) alone has previously been shown to trigger anxiety behavior and robust dendritic hypertrophy of neurons in the basolateral amygdala (BLA). Neurons in the medial prefrontal cortex (mPFC) are also known to be highly sensitive to stress and regulate anxiety-like behaviors. Nevertheless, we know less about acute CORT-induced structural changes of other brain regions and their behavioral outcomes. In addition, the temporal profile of acute CORT effects remains to be examined. The current study investigates time course changes of dendritic architectures in the stress vulnerable brain areas, the BLA and mPFC, and their behavioral consequences after acute treatment with a single dose of CORT. RESULTS: Acute CORT treatment produced delayed onset of dendritic remodeling in the opposite direction in the BLA and mPFC with different time courses. Acute CORT induced dendritic hypertrophy of BLA spiny neurons, which was paralleled by heightened anxiety, both peaked 12 days after the treatment. Meanwhile, CORT-induced dendritic atrophy of mPFC pyramidal neurons peaked on day 6, concomitantly with impaired working memory. Both changed dendritic morphologies and altered behavioral outcomes were fully recovered. CONCLUSION: Our results suggest that stress-induced heightened anxiety appears to be a functional consequence of dendritic remodeling of BLA neurons but not that of mPFC. Instead, stress-induced dendritic atrophy of mPFC neurons is relevant to working memory deficit. Therefore, structural changes in the BLA and the mPFC might be specifically associated with distinct behavioral symptoms observed in stress-related mental disorders. Remarkably, stress-induced dendritic remodeling in the BLA as well as mPFC is readily reversible. The related behavioral outcomes also follow the similar time course in a reversible manner. Therefore, further studies on the cellular mechanism for the plasticity of dendrites architecture might provide new insight into the etiological factors for stress-related mental illness such as posttraumatic stress disorder (PTSD).


Subject(s)
Anxiety/chemically induced , Anxiety/physiopathology , Brain/pathology , Brain/physiopathology , Corticosterone/toxicity , Dendrites/drug effects , Dendrites/pathology , Animals , Anxiety/pathology , Behavior, Animal/drug effects , Brain/drug effects , Male , Rats , Rats, Sprague-Dawley , Tissue Distribution
18.
Exp Mol Med ; 46: e80, 2014 Feb 28.
Article in English | MEDLINE | ID: mdl-24577234

ABSTRACT

Epidemiological studies have suggested an association between pesticide exposure and Parkinson's disease. In this study, we examined the neurotoxicity of an organochlorine pesticide, heptachlor, in vitro and in vivo. In cultured SH-SY5Y cells, heptachlor induced mitochondria-mediated apoptosis. When injected into mice intraperitoneally on a subchronic schedule, heptachlor induced selective loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, the heptachlor injection induced gliosis of microglia and astrocytes selectively in the ventral midbrain area. When the general locomotor activities were monitored by open field test, the heptachlor injection did not induce any gross motor dysfunction. However, the compound induced Parkinsonism-like movement deficits when assessed by a gait and a pole test. These results suggest that heptachlor can induce Parkinson's disease-related neurotoxicities in vivo.


Subject(s)
Apoptosis , Dopaminergic Neurons/drug effects , Heptachlor/toxicity , Locomotion , Pesticides/toxicity , Substantia Nigra/drug effects , Animals , Astrocytes/drug effects , Astrocytes/pathology , Cell Line, Tumor , Cells, Cultured , Dopaminergic Neurons/pathology , Gait , Humans , Mice , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/physiopathology , Parkinsonian Disorders/chemically induced , Substantia Nigra/pathology , Substantia Nigra/physiopathology
19.
Biochem Biophys Res Commun ; 441(4): 799-804, 2013 Nov 29.
Article in English | MEDLINE | ID: mdl-24211575

ABSTRACT

In the present study, we investigated whether a histone deacetylase sirtuin 1 (SIRT1) can regulate the protein stability of homeodomain-interacting protein kinase 2 (HIPK2). We observed the evidence of molecular interaction between SIRT1 and HIPK2. Interestingly, overexpression or pharmacological activation of SIRT1 promoted ubiquitination and the proteasomal degradation of HIPK2 whereas inhibition of SIRT1 activity increased the protein level of HIPK2. Furthermore, a SIRT1 activator decreased the level of HIPK2 acetylation whereas an inhibitor increased the acetylation level. These results suggest that SIRT1 may deacetylate and promote the ubiquitination and subsequent proteasomal degradation of HIPK2.


Subject(s)
Carrier Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Sirtuin 1/metabolism , HEK293 Cells , Humans , Proteasome Endopeptidase Complex/metabolism , Protein Stability , Proteolysis , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/genetics , Ubiquitination
20.
Biochem Biophys Res Commun ; 437(4): 632-6, 2013 Aug 09.
Article in English | MEDLINE | ID: mdl-23867817

ABSTRACT

Environmental toxins like pesticides have been implicated in the pathogenesis of Parkinson's disease (PD). Epidemiological studies suggested that exposures to organochlorine pesticides have an association with an increased PD risk. In the present study, we examined the mechanism of toxicity induced by an organochlorine pesticide heptachlor. In a human dopaminergic neuroblastoma SH-SY5Y cells, heptachlor induced both morphological and functional damages in mitochondria. Interestingly, the compound inhibited mitochondrial electron transport chain complex III activity. Rapid generation of reactive oxygen species and the activation of Bax were then detected. Subsequently, mitochondria-mediated, caspase-dependent apoptosis followed. Our results raise a possibility that an organochlorine pesticide heptachlor can act as a neurotoxicant associated with PD.


Subject(s)
Apoptosis , Electron Transport Complex III/metabolism , Heptachlor/pharmacology , Insecticides/pharmacology , Mitochondria/metabolism , Caspases/metabolism , Cell Line, Tumor , Dopaminergic Neurons/metabolism , Electron Transport Complex III/drug effects , Humans , Mitochondria/drug effects , Neuroblastoma/metabolism , Neuroblastoma/pathology , Reactive Oxygen Species/metabolism , bcl-2-Associated X Protein/metabolism
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