9 results on '"Han Fang Wu"'
Search Results
2. Generational synaptic functions of GABAA receptor β3 subunit deteriorations in an animal model of social deficit
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Ming-Chia Chu, Han-Fang Wu, Chi-Wei Lee, Yueh-Jung Chung, Hsiang Chi, Po See Chen, and Hui-Ching Lin
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GABAAR ,Excitatory/inhibitory imbalance ,Gephyrin ,Generational effect ,Valproate ,Autism spectrum disorder ,Medicine - Abstract
Abstract Background Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. Methods The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. Results Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. Conclusions Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.
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- 2022
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3. Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model
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Cheng Ta Li, Wei Chang Mao, Chi Wei Lee, Yueh Jung Chung, Hui Ching Lin, Han Fang Wu, and Ming Chia Chu
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Male ,Cognitive Neuroscience ,medicine.medical_treatment ,Long-Term Potentiation ,Prefrontal Cortex ,Stimulation ,Inhibitory postsynaptic potential ,Rats, Sprague-Dawley ,Depressive Disorder, Treatment-Resistant ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Animals ,Medicine ,Theta Rhythm ,Prefrontal cortex ,Neuronal Plasticity ,business.industry ,Motor Cortex ,Long-term potentiation ,Evoked Potentials, Motor ,medicine.disease ,Transcranial Magnetic Stimulation ,Antidepressive Agents ,030227 psychiatry ,Transcranial magnetic stimulation ,Synapses ,Excitatory postsynaptic potential ,Antidepressant ,business ,Treatment-resistant depression ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.
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- 2020
4. Ketamine ameliorates severe traumatic event-induced antidepressant-resistant depression in a rat model through ERK activation
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Chi Wei Lee, Han Fang Wu, Cheng Ta Li, Yi Chao Lee, Yi-Ju Chen, Hui Ching Lin, and Yueh Jung Chung
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medicine.medical_specialty ,MAP Kinase Signaling System ,Serotonin reuptake inhibitor ,Prefrontal Cortex ,Amygdala ,Rats, Sprague-Dawley ,Depressive Disorder, Treatment-Resistant ,03 medical and health sciences ,0302 clinical medicine ,Fluoxetine ,Internal medicine ,medicine ,Animals ,Ketamine ,Prefrontal cortex ,Biological Psychiatry ,Depression (differential diagnoses) ,Pharmacology ,Electroshock ,business.industry ,Traumatic stress ,Antidepressive Agents ,030227 psychiatry ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Antidepressant ,business ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Treatment-resistant depression (TRD) is a major public health issue, as it is common for patients with depression to fail to respond to adequate trials of antidepressants. However, a well-established animal model of TRD is still warranted. The present study focused on selective serotonin reuptake inhibitor (SSRI) resistance, and aimed to investigate whether higher levels of traumatic stress caused by greater numbers of foot-shocks may lead to severe depression and to examine the feasibility of this as an animal model of SSRI-resistant depression. To reveal the correlation between traumatic stress and severe depression, rats received 3, 6 and 10 tone (conditioned stimulus, CS)–shock (unconditioned stimulus, US) pairings to mimic mild, moderate, and severe traumatic events, and subsequent depressive-like behaviors and protein immunocontents were analyzed. The antidepressant efficacy was assessed for ketamine and SSRI (i.e., fluoxetine) treatment. We found that only the severe stress group presented depressive-like behaviors. Phosphorylation of extracellular signal-regulated kinases (ERKs) was decreased in the amygdala and prefrontal cortex (PFC). The immunocontents of GluA1 and PSD 95 were increased in the amygdala and decreased in the PFC. Moreover, the glutamate-related abnormalities in the amygdala and PFC were normalized by single-dose (10 mg/kg, i.p.) ketamine treatment. In contrast, the depressive-like behaviors were not reversed by 28 days of fluoxetine treatment (10 mg/kg, i.p.) in the severe stress group. Our data demonstrated that high levels of traumatic stress could lead to SSRI-resistant depressive symptoms through impacts on the glutamatergic system, and that this rat model has the potential to be a feasible animal model of SSRI-resistant depression.
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- 2019
5. D-Cycloserine Ameliorates Autism-Like Deficits by Removing GluA2-Containing AMPA Receptors in a Valproic Acid-Induced Rat Model
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Chi Wei Lee, Po See Chen, Hui Ching Lin, Tzu Feng Wang, Ya Ting Hsu, Yi-Ju Chen, and Han Fang Wu
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0301 basic medicine ,medicine.medical_specialty ,Dendritic spine ,Offspring ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Neuroscience (miscellaneous) ,Neural facilitation ,AMPA receptor ,Amygdala ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Neurology ,Internal medicine ,medicine ,NMDA receptor ,Receptor ,Long-term depression ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Valproic acid (VPA)-exposed rat offspring have demonstrated autism spectrum disorder (ASD) phenotypes and impaired N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala. NMDAR partial agonist D-cycloserine (DCS) has been reported to act as a cognitive enhancer by increasing the NMDAR response to improve autistic-like phenotypes in animals. However, the mechanism of DCS in alleviating the ASD is still unknown. Using combined behavioral, electrophysiological, and molecular approaches, we found that DCS administration rescued social interaction deficits and anxiety/repetitive-like behaviors observed in VPA-exposed offspring. In the amygdala synapses, DCS treatment reversed the decreased paired pulse ratio (PPR) and the impaired NMDAR-dependent LTD, increased the frequency and amplitude of miniature excitatory post-synaptic currents (mEPSCs), and resulted in a higher dendritic spine density at the amygdala synapses in the VPA-exposed offspring. Moreover, we found that DCS facilitated the removal of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA2/AMPARs) by inducing NMDAR-dependent LTD in the VPA-exposed offspring. We further established that the effects of DCS treatment, including increased GluA2/AMPAR removal and rescues of impaired social behavior, were blocked by Tat-GluA23Y, a GluA2-derived peptide that disrupted regulation of AMPAR endocytosis. These results provided the first evidence that rescue of the ASD-like phenotype by DCS is mediated by the mechanism of GluA2/AMPAR removal in VPA-exposed rat offspring.
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- 2017
6. MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat
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Ming-Chia Chu, Sheng Huang Lin, You Yin Chen, Yu Chun Lo, Han-Fang Wu, Ting-Chun Lin, Yin-Chieh Liu, Ching Wen Chang, Ssu-Ju Li, Hui Ching Lin, Chi-Wei Lee, Ting-Chieh Chen, I-Cheng Lin, Yen-Yu Ian Shih, and Yu-Ju Lin
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Male ,Deep brain stimulation ,Mediodorsal Thalamic Nucleus ,Offspring ,Autism Spectrum Disorder ,medicine.medical_treatment ,Autism ,Deep Brain Stimulation ,Biophysics ,Striatum ,behavioral disciplines and activities ,050105 experimental psychology ,lcsh:RC321-571 ,Central thalamic nucleus ,Rats, Sprague-Dawley ,03 medical and health sciences ,Functional connectivity ,0302 clinical medicine ,Dopamine receptor D2 ,medicine ,Animals ,0501 psychology and cognitive sciences ,Interpersonal Relations ,Social behavior ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,health care economics and organizations ,Brain Mapping ,business.industry ,Receptors, Dopamine D2 ,General Neuroscience ,05 social sciences ,medicine.disease ,Magnetic Resonance Imaging ,Social relation ,Rats ,nervous system ,Synaptic plasticity ,Neurology (clinical) ,Nerve Net ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Social deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. Objective We first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model. Methods Brain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. Results The DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. Conclusions Applying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.
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- 2019
7. Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid-Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus
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Su-Zhen Wu, Hui Ching Lin, Yi-Chao Lee, Han-Fang Wu, Chi-Wei Lee, I-Tuan Chen, Chi-Chen Huang, Yi-Ju Chen, Chih-Wei Tang, and Chung-Hsi Hsing
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0301 basic medicine ,Epoxide hydrolase 2 ,medicine.medical_specialty ,Article Subject ,Long-Term Potentiation ,AMPA receptor ,Epoxyeicosatrienoic acid ,Adenosine receptor antagonist ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,lcsh:RC321-571 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,8,11,14-Eicosatrienoic Acid ,Ca2+/calmodulin-dependent protein kinase ,Internal medicine ,medicine ,Cyclic AMP ,Animals ,Receptors, AMPA ,Protein kinase A ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Epoxide Hydrolases ,Neurons ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Neurology ,chemistry ,nervous system ,cardiovascular system ,NMDA receptor ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction - Abstract
Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus.
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- 2017
8. Alleviation of N-Methyl-D-Aspartate Receptor-Dependent Long-Term Depression via Regulation of the Glycogen Synthase Kinase-3β Pathway in the Amygdala of a Valproic Acid-Induced Animal Model of Autism
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Po See Chen, I-Tuan Chen, Han-Fang Wu, Yi-Ju Chen, Hui Ching Lin, and Chi-Wei Lee
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0301 basic medicine ,Offspring ,Neuroscience (miscellaneous) ,Amygdala ,Receptors, N-Methyl-D-Aspartate ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,0302 clinical medicine ,GSK-3 ,medicine ,Animals ,Autistic Disorder ,Enzyme Inhibitors ,Long-term depression ,Glycogen synthase ,Social Behavior ,Glycogen Synthase Kinase 3 beta ,Neuronal Plasticity ,biology ,Depression ,Valproic Acid ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Synaptic plasticity ,biology.protein ,NMDA receptor ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The amygdala plays crucial roles in socio-emotional behavior and cognition, both of which are abnormal in autism spectrum disorder (ASD). Valproic acid (VPA)-exposed rat offspring have demonstrated ASD phenotypes and amygdala excitatory/inhibitory imbalance. However, the role of glutamatergic synapses in this imbalance remains unclear. In this study, we used a VPA-induced ASD-like model to assess glutamatergic synapse-dependent long-term depression (LTD) and depotentiation (DPT) in the amygdala. We first confirmed that the VPA-exposed offspring exhibited sociability deficits, anxiety, depression-like behavior, and abnormal nociception thresholds. Then, electrophysiological examination showed a significantly decreased paired-pulse ratio in the amygdala. In addition, both NMDA-dependent LTD and DPT were absent from the amygdala. Furthermore, we found that the levels of glycogen synthase kinase3β (GSK-3β) phosphorylation and β-catenin were significantly higher in the amygdala of the experimental animals than in the controls. Local infusion of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin into the amygdala reversed the increased phosphorylation level and impaired social behavior. Taken together, the results suggested that NMDA receptor-related synaptic plasticity is dysfunctional in VPA-exposed offspring. In addition, GSK-3β in the amygdala is critical for synaptic plasticity at the glutamatergic synapses and is related to social behavior. Its role in the underlying mechanism of ASD merits further investigation.
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- 2016
9. Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model
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Han-Fang Wu, Yi-Ju Chen, Ya-Ting Hsu, I-Tuan Chen, Hui Ching Lin, Ting-Yi Lu, Po See Chen, and Ming-Chia Chu
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Male ,serotonin system ,0301 basic medicine ,Agonist ,Serotonin ,Deep brain stimulation ,Autism Spectrum Disorder ,medicine.drug_class ,Offspring ,Deep Brain Stimulation ,medicine.medical_treatment ,Prefrontal Cortex ,Receptors, N-Methyl-D-Aspartate ,Article ,Catalysis ,lcsh:Chemistry ,Rats, Sprague-Dawley ,Inorganic Chemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Physical and Theoretical Chemistry ,Prefrontal cortex ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Valproic Acid ,business.industry ,Organic Chemistry ,General Medicine ,Serotonin 5-HT1 Receptor Agonists ,Receptors, GABA-A ,medicine.disease ,Receptor antagonist ,Rats ,Computer Science Applications ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,nervous system ,Autism ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the &beta, 3 subunit of &gamma, aminobutyric acid type A receptors (GABAAR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC.
- Published
- 2018
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