Publications by authors named "Yong-Chul Bae"

165 Publications

Correction: Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus.

Cell Death Dis 2021 Jun 1;12(6):565. Epub 2021 Jun 1.

Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam, 52727, Republic of Korea.

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http://dx.doi.org/10.1038/s41419-021-03841-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169749PMC
June 2021

Ablation of dynamin-related protein 1 promotes diabetes-induced synaptic injury in the hippocampus.

Cell Death Dis 2021 May 5;12(5):445. Epub 2021 May 5.

Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam, 52727, Republic of Korea.

Dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction is associated with synaptic injury in the diabetic brain. However, the dysfunctional mitochondria by Drp1 deletion in the diabetic brain are poorly understood. Here, we investigated the effects of neuron-specific Drp1 deletion on synaptic damage and mitophagy in the hippocampus of a high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. HFD/STZ-induced diabetic mice exhibited metabolic disturbances and synaptic damages. Floxed Drp1 mice were crossed with Ca/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre mice, to generate neuron-specific Drp1 knockout (Drp1cKO) mice, which showed marked mitochondrial swelling and dendritic spine loss in hippocampal neurons. In particular, diabetic Drp1cKO mice exhibited an increase in dendritic spine loss and higher levels of oxidative stress and neuroinflammation compared with diabetic wild-type (WT) mice. Diabetic WT mice generally displayed increased Drp1-induced small mitochondrial morphology in hippocampal neurons, but large mitochondria were prominently observed in diabetic Drp1cKO mice. The levels of microtubule-associated protein 1 light-chain 3 and lysosomal-associated membrane protein 1 proteins were significantly increased in the hippocampus of diabetic Drp1cKO mice compared with diabetic WT mice. The inhibition of Drp1 adversely promotes synaptic injury and neurodegeneration in the diabetic brain. The findings suggest that the exploratory mechanisms behind Drp1-mediated mitochondrial dysfunction could provide a possible therapeutic target for diabetic brain complications.
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http://dx.doi.org/10.1038/s41419-021-03723-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099876PMC
May 2021

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.
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http://dx.doi.org/10.3390/ijms22041915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919013PMC
February 2021

More Teeth and Posterior Balanced Occlusion Are a Key Determinant for Cognitive Function in the Elderly.

Int J Environ Res Public Health 2021 02 19;18(4). Epub 2021 Feb 19.

Department of Preventive Dentistry, Kyungpook National University School of Dentistry, Daegu 41940, Korea.

Age-related decline in cognitive function is a major challenge in geriatric healthcare. A possible explanation is that the tooth loss or low chewing ability is at cause of cognitive impairment or dementia. The study aimed to investigate the potential relationship between chewing ability and cognitive function in the elderly. A total of 563 participants aged 65 years or over residing in urban and rural areas of South Korea were surveyed. The chewing ability was measured by objectively measurable indications such as the number of remaining teeth, denture status, color-changeable gum, and occlusal balance using T-Scan III. The cognitive function was measured by the Korean version of Mini-Mental State Examination-Dementia Screening (MMSE-DS) and a score of 24 or more (out of 30) indicates a normal cognition, below 23 indicates cognitive impairment. The association between socio-demographic factors, chewing ability factors, and cognitive function demonstrated statistically significant results. When comparing the denture status and chewing ability, the proportion of need denture group had fewer remaining teeth and anterior balanced occlusion. The average number of remaining teeth in anterior balanced occlusion with cognitive impairment was 11.2 compared to posterior balanced occlusion with the normal cognition 19.2. A multiple linear regression analysis declared a significant correlation between number of remaining teeth, denture status, occlusal balance, and cognitive function. Results of the present study revealed objectively measurable indications are suitable for chewing ability assessment and correlated with cognitive function.
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http://dx.doi.org/10.3390/ijerph18041996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922962PMC
February 2021

Widespread corticopetal projections from the oval paracentral nucleus of the intralaminar thalamic nuclei conveying orofacial proprioception in rats.

Brain Struct Funct 2021 May 4;226(4):1115-1133. Epub 2021 Feb 4.

Department of Oral Anatomy and Neurobiology, Osaka University Graduate School of Dentistry, Suita, Osaka, 565-0871, Japan.

The oval paracentral nucleus (OPC) was initially isolated from the paracentral nucleus (PC) within the intralaminar thalamic nuclei in rats. We have recently shown that the rat OPC receives proprioceptive inputs from jaw-closing muscle spindles (JCMSs). However, it remains unknown which cortical areas receive thalamic inputs from the OPC, and whether the cortical areas receiving the OPC inputs are distinct from those receiving inputs from the other intralaminar nuclei and sensory thalamic nuclei. To address this issue, we injected an anterograde tracer, biotinylated dextranamine (BDA), into the OPC, which was electrophysiologically identified by recording of proprioceptive inputs from the JCMSs. Many BDA-labeled axonal fibers and terminals from the OPC were ipsilaterally observed in the rostral and rostroventral regions of the primary somatosensory cortex (S1), the rostral region of the secondary somatosensory cortex (S2), and the most rostrocaudal levels of the granular insular cortex (GI). In contrast, a BDA injection into the caudal PC, which was located slightly rostral to the OPC, resulted in ipsilateral labeling of axonal fibers and terminals in the rostrolateral region of the medial agranular cortex and the rostromedial region of the lateral agranular cortex. Furthermore, injections of a retrograde tracer, Fluorogold, into these S1, S2, and GI regions, resulted in preferential labeling of neurons in the ipsilateral OPC among the intralaminar and sensory thalamic nuclei. These findings reveal that the rat OPC has widespread, but strong corticopetal projections, indicating that there exist divergent corticopetal pathways from the intralaminar thalamic nucleus, which process JCMS proprioceptive sensation.
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http://dx.doi.org/10.1007/s00429-021-02228-5DOI Listing
May 2021

Development of γ-aminobutyric acid-, glycine-, and glutamate-immunopositive boutons on the rat genioglossal motoneurons.

Brain Struct Funct 2021 Apr 21;226(3):889-900. Epub 2021 Jan 21.

Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, 188-1, 2-Ga, Samdeok-Dong, Jung-Gu, Daegu, 700-412, Korea.

Detailed information about the development of excitatory and inhibitory synapses on the genioglossal (GG) motoneuron may help to understand the mechanism of fine control of GG motoneuron firing and the coordinated tongue movement during postnatal development. For this, we investigated the development of γ-aminobutyric acid (GABA)-immunopositive (GABA +), glycine + (Gly +), and glutamate + (Glut +) axon terminals (boutons) on the somata of rat GG motoneurons at a postnatal day 2 (P2), P6 and P18 by retrograde labeling of GG motoneurons with horseradish peroxidase, electron microscopic postembedding immunogold staining with GABA, Gly, and Glut antisera, and quantitative analysis. The number of boutons per GG motoneuron somata and the mean length of bouton apposition, measures of bouton size and synaptic covering percentage, were significantly increased from P2/P6 to P18. The number and fraction of GABA + only boutons of all boutons decreased significantly, whereas those of Gly + only boutons increased significantly from P2/P6 to P18, suggesting developmental switch from GABAergic to glycinergic synaptic transmission. The fraction of mixed GABA +/Gly + boutons of all boutons was the highest among inhibitory bouton types throughout the postnatal development. The fractions of excitatory and inhibitory boutons of all boutons remained unchanged during postnatal development. These findings reveal a distinct developmental pattern of inhibitory synapses on the GG motoneurons different from that on spinal or trigeminal motoneurons, which may have an important role in the regulation of the precise and coordinated movements of the tongue during the maturation of the oral motor system.
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http://dx.doi.org/10.1007/s00429-021-02216-9DOI Listing
April 2021

SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function.

EMBO Mol Med 2021 Feb 11;13(2):e12632. Epub 2021 Jan 11.

Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.

Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co-agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β-catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide-induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.
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http://dx.doi.org/10.15252/emmm.202012632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863395PMC
February 2021

Secretoneurin, a Neuropeptide, Enhances Bone Regeneration in a Mouse Calvarial Bone Defect Model.

Tissue Eng Regen Med 2021 04 3;18(2):315-324. Epub 2020 Nov 3.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940, Republic of Korea.

Background: This study investigates the effects of a neuropeptide, secretoneurin (SN), on bone regeneration in an experimental mouse model.

Methods: The effects of SN on cell proliferation, osteoblast marker genes expression, and mineralization were evaluated using the CCK-8 assay, quantitative reverse transcriptase polymerase chain reaction (RT-PCR), and alizarin red S staining, respectively. To examine the effects of SN on bone regeneration in vivo, bone defects were created in the calvaria of ICR mice, and 0.5 or 1 µg/ml SN was applied. New bone formation was analyzed by micro-computed tomography (micro-CT) and histology. New blood vessel formation was assessed by CD34 immunohistochemistry.

Results: SN had no significant effect on proliferation and mineralization of MC3T3-E1 cells. However, SN partially induced the gene expression of osteoblast differentiation markers such as runt-related transcription factor 2, alkaline phosphatase, collagen type I alpha 1, and osteopontin. A significant increase of bone regeneration was observed in SN treated calvarial defects. The bone volume (BV), BV/tissue volume, trabecular thickness and trabecular number values were significantly increased in the collagen sponge plus 0.5 or 1 µg/ml SN group (p < 0.01) compared with the control group. Histologic analysis also revealed increased new bone formation in the SN-treated groups. Immunohistochemical staining of CD34 showed that the SN-treated groups contained more blood vessels compared with control in the calvarial defect area.

Conclusion: SN increases new bone and blood vessel formation in a calvarial defect site. This study suggests that SN may enhance new bone formation through its potent angiogenic activity.
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http://dx.doi.org/10.1007/s13770-020-00304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012437PMC
April 2021

Astrocytes Control Sensory Acuity via Tonic Inhibition in the Thalamus.

Neuron 2020 11 8;108(4):691-706.e10. Epub 2020 Sep 8.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea; POSTECH Biotech Center, POSTECH, Pohang, South Korea. Electronic address:

Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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http://dx.doi.org/10.1016/j.neuron.2020.08.013DOI Listing
November 2020

Proprioceptive thalamus receiving forelimb and neck muscle spindle inputs via the external cuneate nucleus in the rat.

Brain Struct Funct 2020 Sep 3;225(7):2177-2192. Epub 2020 Aug 3.

Department of Oral Anatomy and Neurobiology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Proprioceptive signals from body muscles have historically been considered to project to the rostrodorsal shell of the ventrobasal thalamic complex [the ventral posterolateral nucleus (VPL) and ventral posteromedial nucleus (VPM)]. However, we have recently found that proprioception from rat jaw-closing muscle spindles (JCMSs) is conveyed via the supratrigeminal nucleus to the caudo-ventromedial edge of the VPM, but not to the rostrodorsal shell of the VPM. Therefore, proprioception from other body muscles may also project to thalamic regions other than the rostrodorsal shell of the VPL. We thus examined the thalamic projection from the rat external cuneate nucleus (ECu), which receives proprioceptive inputs from forelimb and neck muscles. After injection of anterograde tracer into the ECu, axon terminals were contralaterally labeled in the ventromedial part (VPLvm) of the VPL, but not in the rostrodorsal shell of the VPL. After anterograde tracer injection into the cuneate nucleus (Cu), axon terminals were widely labeled in the contralateral VPL including the VPLvm. In the VPLvm, we electrophysiologically confirmed the proprioceptive inputs responsive to electrical stimulation of the ECu or median nerve and to the pressure of forelimb/neck muscles or wrist flexion. After retrograde tracer injection into the VPLvm, neurons were contralaterally labeled in the ECu and Cu. After retrograde tracer injection into the VPL where no such proprioceptive inputs were recorded, no ECu neurons were labeled. These findings indicate that proprioception from forelimb/neck muscle spindles and JCMSs is somatotopically transmitted to the ventromedial floor of the ventrobasal thalamic complex, but not to its rostrodorsal shell.
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http://dx.doi.org/10.1007/s00429-020-02118-2DOI Listing
September 2020

Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea.

Evidence has mounted that insulin can be synthesized in various brain regions, including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotropin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS-induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone (Gh) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the downregulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS-induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin.
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http://dx.doi.org/10.1172/jci.insight.135412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455129PMC
August 2020

Parvalbumin-, substance P- and calcitonin gene-related peptide-immunopositive axons in the human dental pulp differ in their distribution of varicosities.

Sci Rep 2020 06 30;10(1):10672. Epub 2020 Jun 30.

Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, 188-1, 2-Ga, Samdeok-Dong, Jung-Gu, Daegu, 41940, Korea.

Information on the frequency and spatial distribution of axonal varicosities associated with release of neurotransmitters in the dental pulp is important to help elucidate the peripheral mechanisms of dental pain, mediated by myelinated versus unmyelinated fibers. For this, we investigated the distribution of axonal varicosities in the human dental pulp using light- and electron-microscopic immunohistochemistry for the vesicular glutamate transporter 2 (VGLUT2), which is involved in the glutamatergic transmission, and syntaxin-1 and synaptosomal nerve-associated protein 25 (SNAP-25), combined with parvalbumin (PV), which is expressed mostly in myelinated axons, and substance P (SP) and calcitonin gene-related peptide (CGRP), which are expressed mostly in unmyelinated axons. We found that the varicosities of the SP- and CGRP-immunopositive (+) axons were uniformly distributed throughout the dental pulp, whereas those of PV+ axons were only dense in the peripheral pulp, and that the expression of PV, VGLUT2, syntaxin-1, SNAP-25, SP and CGRP was significantly higher in the varicosities than in the axonal segments between them. These findings are consistent with the release of glutamate and neuropeptides by axonal varicosities of SP+ and CGRP+ unmyelinated fibers, involved in pulpal pain throughout the human dental pulp, and by varicosities of PV+ fibers, arising from parent myelinated fibers, and involved in dentin sensitivity primarily in the peripheral pulp.
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http://dx.doi.org/10.1038/s41598-020-67804-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327034PMC
June 2020

Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice.

PLoS Biol 2020 04 30;18(4):e3000717. Epub 2020 Apr 30.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.
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http://dx.doi.org/10.1371/journal.pbio.3000717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217483PMC
April 2020

Splice-dependent trans-synaptic PTPδ-IL1RAPL1 interaction regulates synapse formation and non-REM sleep.

EMBO J 2020 06 29;39(11):e104150. Epub 2020 Apr 29.

Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.

Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.
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http://dx.doi.org/10.15252/embj.2019104150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265247PMC
June 2020

Wnt-PLC-IP-Connexin-Ca axis maintains ependymal motile cilia in zebrafish spinal cord.

Nat Commun 2020 04 20;11(1):1860. Epub 2020 Apr 20.

Department of Biomedical Sciences, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea.

Ependymal cells (ECs) are multiciliated neuroepithelial cells that line the ventricles of the brain and the central canal of the spinal cord (SC). How ependymal motile cilia are maintained remains largely unexplored. Here we show that zebrafish embryos deficient in Wnt signaling have defective motile cilia, yet harbor intact basal bodies. With respect to maintenance of ependymal motile cilia, plcδ3a is a target gene of Wnt signaling. Lack of Connexin43 (Cx43), especially its channel function, decreases motile cilia and intercellular Ca wave (ICW) propagation. Genetic ablation of cx43 in zebrafish and mice diminished motile cilia. Finally, Cx43 is also expressed in ECs of the human SC. Taken together, our findings indicate that gap junction mediated ICWs play an important role in the maintenance of ependymal motile cilia, and suggest that the enhancement of functional gap junctions by pharmacological or genetic manipulations may be adopted to ameliorate motile ciliopathy.
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http://dx.doi.org/10.1038/s41467-020-15248-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170879PMC
April 2020

Ascending projection of jaw-closing muscle-proprioception to the intralaminar thalamic nuclei in rats.

Brain Res 2020 07 9;1739:146830. Epub 2020 Apr 9.

Department of Oral Anatomy and Neurobiology, Graduate School of Dentistry, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address:

An invasive intralaminar thalamic stimulation and a non-invasive application of oral splint are both effective in treating tic symptoms of patients with Tourette syndrome (TS). Therefore, these two treatments may exert some influence on the same brain region in TS patients. We thus hypothesized that the proprioceptive input arising from the muscle spindles of jaw-closing muscles (JCMSs), known to be increased by the application of oral splint, is transmitted to the intralaminar thalamic nuclei. To test this issue, we morphologically and electrophysiologically examined the thalamic projections of proprioceptive input from the JCMSs to the intralaminar thalamic nuclei of rats. We first injected an anterograde tracer, biotinylated dextranamine, into the electrophysiologically identified supratrigeminal nucleus, which is known to receive proprioceptive inputs from the JCMSs via the trigeminal mesencephalic neurons. A moderate number of biotinylated dextranamine-labeled axon terminals were bilaterally distributed in the oval paracentral nucleus (OPC) of the intralaminar thalamic nuclei. We also detected electrophysiological responses to the electrical stimulation of bilateral masseter nerves and to sustained jaw-opening in the OPC. After injection of retrograde tracer (cholera toxin B subunit or Fluorogold) into the OPC, neuronal cell bodies were retrogradely labeled in the rostrodorsal portion of the bilateral supratrigeminal nucleus. Here, we show that proprioceptive inputs from the JCMSs are conveyed to the OPC in the intralaminar nuclei via the supratrigeminal nucleus. This study can help to understand previously unrecognized pathways of proprioception ascending inputs from the brainstem to the thalamus, which may contribute to treatments of TS patients.
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http://dx.doi.org/10.1016/j.brainres.2020.146830DOI Listing
July 2020

Morphological foundations of pain processing in dental pulp.

J Oral Sci 2020 ;62(2):126-130

Department of Oral Anatomy and Neurobiology, Graduate School of Dentistry, Osaka University.

Dental pulp is densely innervated by sensory afferents that are primarily involved in nociception. Elucidating the type and properties of these afferents and their distribution patterns within the dental pulp is crucial for understanding the mechanisms of acute dental pain and dental hypersensitivity. Recent studies on the release of the transmitter glutamate and the expression of glutamate receptors and vesicular glutamate transporters (VGLUT) in the pulpal axons and trigeminal ganglion (TG) have suggested the possibility of a distinct glutamate signaling mechanism underlying the peripheral processing of dental pain. This review discusses recent findings on the innervation of dental pulp and glutamate signaling by pulpal axons. First, recent findings on the morphological features and types of axons innervating the dental pulp are summarized. Then, glutamate signaling in the dental pulp and changes in the expression of VGLUT1 and VGLUT2 in the pulpal axons and TG neurons following pulpal inflammation are explained. Finally, findings on glutamate release from odontoblasts are briefly described.
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http://dx.doi.org/10.2334/josnusd.19-0451DOI Listing
April 2020

Presynaptic PTPσ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms.

Elife 2020 03 6;9. Epub 2020 Mar 6.

Department of Biological Sciences, KAIST, Daejeon, Republic of Korea.

Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTPσ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-synaptic adhesions of PTPσ, suggesting that the cytoplasmic domains of PTPσ, known to have tyrosine phosphatase activity and mediate protein-protein interactions, are important. In line with this, phosphotyrosine levels of presynaptic proteins, including neurexin-1, are strongly increased in PTPσ-mutant mice. Behaviorally, PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition. These results suggest that presynaptic PTPσ regulates postsynaptic NMDAR function through trans-synaptic and direct adhesion-independent mechanisms and novelty recognition in social and reward contexts.
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http://dx.doi.org/10.7554/eLife.54224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069723PMC
March 2020

Increasing ERK phosphorylation by inhibition of p38 activity protects against cadmium-induced apoptotic cell death through ERK/Drp1/p38 signaling axis in spermatocyte-derived GC-2spd cells.

Toxicol Appl Pharmacol 2019 12 30;384:114797. Epub 2019 Oct 30.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Many studies report that cadmium chloride (CdCl)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl exposure, resulting in increased apoptotic cell death. Moreover, CdCl-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl-induced male infertility.
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http://dx.doi.org/10.1016/j.taap.2019.114797DOI Listing
December 2019

Ultrasonic Neuromodulation via Astrocytic TRPA1.

Curr Biol 2019 10 3;29(20):3386-3401.e8. Epub 2019 Oct 3.

Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address:

Low-intensity, low-frequency ultrasound (LILFU) is the next-generation, non-invasive brain stimulation technology for treating various neurological and psychiatric disorders. However, the underlying cellular and molecular mechanism of LILFU-induced neuromodulation has remained unknown. Here, we report that LILFU-induced neuromodulation is initiated by opening of TRPA1 channels in astrocytes. The Ca entry through TRPA1 causes a release of gliotransmitters including glutamate through Best1 channels in astrocytes. The released glutamate activates NMDA receptors in neighboring neurons to elicit action potential firing. Our results reveal an unprecedented mechanism of LILFU-induced neuromodulation, involving TRPA1 as a unique sensor for LILFU and glutamate-releasing Best1 as a mediator of glia-neuron interaction. These discoveries should prove to be useful for optimization of human brain stimulation and ultrasonogenetic manipulations of TRPA1.
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http://dx.doi.org/10.1016/j.cub.2019.08.021DOI Listing
October 2019

Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling.

Redox Biol 2020 01 3;28:101315. Epub 2019 Sep 3.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea; School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea. Electronic address:

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD-which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma-is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role in regulating adipogenesis and suggested the need to further investigation on the potential curative effects of Prx5 on obesity-induced fatty liver disease. In the present study, we focused on the role of Prx5 in fatty liver disease. We found that Prx5 overexpression significantly suppressed cytosolic and mitochondrial ROS generation. Additionally, Prx5 regulated the AMP-activated protein kinase pathway and lipogenic gene (sterol regulatory element binding protein-1 and FAS) expression; it also inhibited lipid accumulation, resulting in the amelioration of free fatty acid-induced hepatic steatosis. Silence of Prx5 triggered de novo lipogenesis and abnormal lipid accumulation in HepG2 cells. Concordantly, Prx5 knockout mice exhibited a high susceptibility to obesity-induced hepatic steatosis. Liver sections of Prx5-deletion mice fed on a high-fat diet displayed Oil Red O-stained dots and small leaky shapes due to immoderate fat deposition. Collectively, our findings suggest that Prx5 functions as a protective regulator in fatty liver disease and that it may be a valuable therapeutic target for the management of obesity-related metabolic diseases.
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http://dx.doi.org/10.1016/j.redox.2019.101315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736789PMC
January 2020

Vesicular Glutamate Transporter 1 (VGLUT1)- and VGLUT2-containing Terminals on the Rat Jaw-closing γ-Motoneurons.

Exp Neurobiol 2019 Aug;28(4):451-457

Department of Anatomy and Neurobiology, Kyungpook National University, Daegu 41940, Korea.

Currently, compared to jaw-closing (JC) α-motoneurons, the information on the distribution and morphology of glutamatergic synapses on the jaw-closing (JC) γ-motoneurons, which may help elucidate the mechanism of isometric contraction of the JC muscle, is very limited. This study investigated the distribution and ultrastructural features of vesicular glutamate transporter 1 (VGLUT1)- and VGLUT2-immunopositive (+) axon terminals (boutons) on JC γ-motoneurons by retrograde tracing with horseradish peroxidase, electron microscopic immunocytochemistry, and quantitative analysis. About 35% of the boutons on identified JC γ-motoneurons were VGLUT+, and of those, 99% were VGLUT2+. The fraction of VGLUT1+ boutons of all boutons and the percentage of membrane of JC γ-motoneurons covered by these boutons were significantly lower than those for the JC α-motoneurons, revealed in our previous work. The bouton volume, mitochondrial volume, and active zone area of the VGLUT2+ boutons on the JC γ-motoneurons were uniformly small. These findings suggest that the JC γ-motoneurons, in contrast to the JC α-motoneurons, receive generally weak glutamatergic synaptic input almost exclusively from VGLUT2+ premotoneurons that form direct synapse with motoneurons.
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http://dx.doi.org/10.5607/en.2019.28.4.451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751869PMC
August 2019

Parkin in early stage LPS-stimulated BV-2 cells regulates pro-inflammatory response and mitochondrial quality via mitophagy.

J Neuroimmunol 2019 11 28;336:577044. Epub 2019 Aug 28.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jneuroim.2019.577044DOI Listing
November 2019

Paradoxical role of lipocalin-2 in metabolic disorders and neurological complications.

Biochem Pharmacol 2019 11 30;169:113626. Epub 2019 Aug 30.

Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biomedical Science, BK21 PLUS KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Lipocalin-2 (LCN2), also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), is a 25-kDa secreted protein implicated in various metabolic and inflammatory diseases. Early studies suggest the protective function of LCN2 in which it acts as a bacteriostatic agent that competes with bacteria for iron-bound siderophores. However, both detrimental and beneficial roles of LCN2 have recently been documented in metabolic and neuroinflammatory diseases. Metabolic inflammation, as observed in diabetes and obesity, has been closely associated with the upregulation of LCN2 in blood plasma and several tissues in both humans and rodents, suggesting its pro-diabetic and pro-obesogenic role. On the contrary, other studies imply an anti-diabetic and anti-obesogenic role of LCN2 whereby a deficiency in the Lcn2 gene results in the impairment of insulin sensitivity and enhances the high-fat-diet-induced expansion of fat. A similar dual role of LCN2 has also been reported in various animal models for neurological disorders. In the midst of these mixed findings, there is no experimental evidence to explain why LCN2 shows such a contrasting role in the various studies. This debate needs to be resolved (or reconciled) and an integrated view on the topic is desirable. Herein, we attempt to address this issue by reviewing the recent findings on LCN2 in metabolic disorders and assess the potential cellular or molecular mechanisms underlying the dual role of LCN2. We further discuss the possibilities and challenges of targeting LCN2 as a potential therapeutic strategy for metabolic disorders and neurological complications.
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http://dx.doi.org/10.1016/j.bcp.2019.113626DOI Listing
November 2019

Peroxiredoxin 5 prevents diethylhexyl phthalate-induced neuronal cell death by inhibiting mitochondrial fission in mouse hippocampal HT-22 cells.

Neurotoxicology 2019 09 10;74:242-251. Epub 2019 Aug 10.

School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Diethylhexyl phthalate (DEHP) is used in many plastic products, such as perfumes, lunch boxes, bags, and building materials. As DEHP is not covalently bound to the plastic, humans can be easily exposed to it. DEHP induces neurobehavioral changes and neuronal cell death; however, the exact mechanism behind this is still unclear. We hypothesized that the neurotoxic mechanism is related to DEHP-induced oxidative stress leading to apoptosis through mitochondrial fission. We demonstrated that DEHP-induced oxidative stress triggers neuronal cell death via mitochondrial fission in mouse hippocampal HT-22 cells. Furthermore, we identified that peroxiredoxin 5 (Prx5), an antioxidant enzyme induced by DEHP, prevents DEHP-induced mitochondrial fission by inhibiting the production of reactive oxygen species. We conclude that Prx5 may be a promising therapeutic target for mitigating DEHP-induced neuronal cell death.
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http://dx.doi.org/10.1016/j.neuro.2019.08.003DOI Listing
September 2019

Activation of Astrocytic μ-Opioid Receptor Causes Conditioned Place Preference.

Cell Rep 2019 07;28(5):1154-1166.e5

Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Department of Neuroscience, Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea; Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea. Electronic address:

The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.
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http://dx.doi.org/10.1016/j.celrep.2019.06.071DOI Listing
July 2019

Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells.

Mol Cell Biol 2019 10 27;39(20). Epub 2019 Sep 27.

School of Life Science, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea

Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.
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http://dx.doi.org/10.1128/MCB.00148-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766699PMC
October 2019

Axon Guidance Molecules Guiding Neuroinflammation.

Exp Neurobiol 2019 Jun 26;28(3):311-319. Epub 2019 Jun 26.

Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Axon guidance molecules (AGMs), such as Netrins, Semaphorins, and Ephrins, have long been known to regulate axonal growth in the developing nervous system. Interestingly, the chemotactic properties of AGMs are also important in the postnatal period, such as in the regulation of immune and inflammatory responses. In particular, AGMs play pivotal roles in inflammation of the nervous system, by either stimulating or inhibiting inflammatory responses, depending on specific ligand-receptor combinations. Understanding such regulatory functions of AGMs in neuroinflammation may allow finding new molecular targets to treat neurodegenerative diseases, in which neuroinflammation underlies aetiology and progression.
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http://dx.doi.org/10.5607/en.2019.28.3.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614065PMC
June 2019

Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitability and Seizure Susceptibility.

Front Mol Neurosci 2019 18;12:155. Epub 2019 Jun 18.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.

Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania. Here we generated and characterized a knock-in mouse line carrying the Q321R mutation ( mice) identified in a human individual with ASD that affects the ankyrin repeat region (ARR) domain of the Shank3 protein. Homozygous mice show a selective decrease in the level of Shank3a, an ARR-containing protein variant, but not other variants. CA1 pyramidal neurons in the hippocampus show decreased neuronal excitability but normal excitatory and inhibitory synaptic transmission. Behaviorally, mice show moderately enhanced self-grooming and anxiolytic-like behavior, but normal locomotion, social interaction, and object recognition and contextual fear memory. In addition, these mice show abnormal electroencephalogram (EEG) patterns and decreased susceptibility to induced seizures. These results indicate that the Q321R mutation alters Shank3 protein stability, neuronal excitability, repetitive and anxiety-like behavior, EEG patterns, and seizure susceptibility in mice.
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http://dx.doi.org/10.3389/fnmol.2019.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591539PMC
June 2019