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Chao Dong, Ji-Chun Zhang, Wei Yao, Qian Ren, Min Ma, Chun Yang, Shigeyuki Chaki, Kenji Hashimoto
BACKGROUND: Similar to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist, MGS0039 shows antidepressant effects. However, there are no reports comparing these two compounds in the social defeat stress model of depression. METHODS: We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice, after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor (BDNF), TrkB, phospho-TrkB (p-TrkB), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (GluA1) and postsynaptic density protein 95 (PSD-95), and dendritic spine density in selected brain regions were measured...
October 7, 2016: International Journal of Neuropsychopharmacology
Nils Rademacher, Bettina Schmerl, Jennifer A Lardong, Markus C Wahl, Sarah A Shoichet
At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons...
October 19, 2016: Scientific Reports
Vivian B Neis, Luis E B Bettio, Morgana Moretti, Priscila B Rosa, Camille M Ribeiro, Andiara E Freitas, Filipe M Gonçalves, Rodrigo B Leal, Ana Lúcia S Rodrigues
Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants...
October 12, 2016: Pharmacology, Biochemistry, and Behavior
Jisung Kim, Siyoung Lee, Bo-Ryoung Choi, Hee Yang, Youjin Hwang, Jung Han Yoon Park, Frank M LaFerla, Jung-Soo Han, Ki Won Lee, Jiyoung Kim
SCOPE: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. We investigated the effect of sulforaphane, a hydrolysis product of glucoraphanin present in Brassica vegetables, on neuronal BDNF expression and its synaptic signaling pathways. METHODS AND RESULTS: Mouse primary cortical neurons and a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD) were used to study the effect of sulforaphane...
October 13, 2016: Molecular Nutrition & Food Research
Eléonore Beurel, Steven F Grieco, Celeste Amadei, Kimberlee Downey, Richard S Jope
OBJECTIVES: Sub-anesthetic doses of ketamine have been found to provide rapid antidepressant actions, indicating that the cellular signaling systems targeted by ketamine are potential sites for therapeutic intervention. Ketamine acts as an antagonist of N-methyl-D-aspartate (NMDA) receptors, and animal studies indicate that subsequent augmentation of signaling by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors is critical for the antidepressant outcome. METHODS: In this study, we tested if the inhibitory effect of ketamine on glycogen synthase kinase-3 (GSK3) affected hippocampal cell-surface AMPA receptors using immunoblotting of membrane and synaptosomal extracts from wild-type and GSK3 knockin mice...
September 30, 2016: Bipolar Disorders
Hui Li, Linjuan-Li, Yaping Wang
Neuronal plasticity in hippocampal neurons is closely related to memory, mood and behavior as well as in the development of depression. Granulocyte colony-stimulating factor (G-CSF) can promote neuronal plasticity and enhance motor skills. However, the function of G-CSF in depression remains poorly understood. In this study, we explored the biological role and potential molecular mechanism of G-CSF on depression-like behaviors. Our results showed that G-CSF was significantly downregulated in the hippocampus of chronic unexpected mild stress (CUMS) rats...
October 28, 2016: Biochemical and Biophysical Research Communications
Marta Domínguez-Prieto, Ana Velasco, Lourdes Vega, Arantxa Tabernero, José M Medina
Amyloid-β (Aβ), Aβ40, Aβ42, and, recently, Aβ25-35 have been directly implicated in the pathogenesis of Alzheimer's disease. We have studied the effects of Aβ on neuronal death, reactive oxygen species (ROS) production, and synaptic assembling in neurons in primary culture. Aβ25-35, Aβ40, and Aβ42 significantly decreased neuronal viability, although Aβ25-35 showed a higher effect. Aβ25-35 showed a more penetrating ability to reach mitochondria while Aβ40 did not enter the neuronal cytosol and Aβ42 was scarcely internalized...
September 17, 2016: Journal of Alzheimer's Disease: JAD
Anna Rafalo-Ulinska, Joanna Piotrowska, Agata Kryczyk, Włodzimierz Opoka, Magdalena Sowa-Kucma, Paulina Misztak, Grazyna Rajkowska, Craig A Stockmeier, Wojciech Datka, Gabriel Nowak, Bernadeta Szewczyk
BACKGROUND: Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein...
September 13, 2016: Journal of Psychiatric Research
Mohammed M Nooh, Salvatore Mancarella, Suleiman W Bahouth
ß1-adrenergic receptor (ß1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The ß1-AR like other G protein-couple receptors (GPCR) is endocytosed in response to intense agonist activation. Recycling of the agonist-internalized ß1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine(312) in the third intracellular loop of the ß1-AR. Progressive elongation of the ß1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the ß1-AR...
September 16, 2016: Biochemical Pharmacology
U Lalo, O Palygin, A Verkhratsky, S G N Grant, Y Pankratov
Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca(2+)-dependent mechanism...
2016: Scientific Reports
Ying Luo, Shengnan Kuang, Lai Xue, Junqing Yang
OBJECTIVES: To examine the mechanism of 5-lipoxygenase (5-LO) in the learning and memory dysfunction in rats subjected to chronic unpredictable mild stress (CUMS). METHODS: Eighty rats were divided into eight groups: the 0.5% sodium carboxymethyl cellulose solution (NaCMC)-treated group, empty vector (LV-Mock)-treated group, CUMS+NaCMC-treated group, CUMS+sertraline-treated group, CUMS+caffeic acid (10mg/kg)-treated group, CUMS+caffeic acid (30mg/kg)-treated group, CUMS+LV-Mock-treated group, and CUMS+5-LO-silencers lentiviral vectors (LV-si-5-LO)-treated group, n=10...
September 14, 2016: Physiology & Behavior
Dayton J Goodell, Megan A Ahern, Jessica Baynard, Vanessa L Wall, Sondra T Bland
Post-weaning social isolation (PSI) has been shown to increase aggressive behavior and alter medial prefrontal cortex (mPFC) function in social species such as rats. Here we developed a novel escapable social interaction test (ESIT) allowing for the quantification of escape and social behaviors in addition to mPFC activation in response to an aggressive or nonaggressive stimulus rat. Male rats were exposed to 3 weeks of PSI (ISO) or group (GRP) housing, and exposed to 3 trials, with either no trial, all trials, or the last trial only with a stimulus rat...
September 12, 2016: Behavioural Brain Research
Olalekan M Ogundele, Charles C Lee, Joseph Francis
Modifications to neural circuits of the paraventricular hypothalamic nucleus (PVN) have been implicated in sympathoexcitation and systemic cardiovascular dysfunction. However, to date, the role of insulin-like growth factor 1 receptor (IGF-1R) expression on PVN pathophysiology is unknown. Using confocal immunofluorescence quantification and electrophysiological recordings from acute PVN slices, we investigated the mechanism through which age-dependent IGF-1R depletion contributes to the progression of inflammation and sympathoexcitation in the PVN of spontaneously hypertensive rats (SHR)...
September 14, 2016: Journal of Neurochemistry
Ward G Walkup, Tara L Mastro, Leslie T Schenker, Jost Vielmetter, Rebecca Hu, Ariella Iancu, Meera Reghunathan, Barry Dylan Bannon, Mary B Kennedy
SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins...
September 13, 2016: ELife
Prapimpun Wongchitrat, Niyada Lansubsakul, Utcharaporn Kamsrijai, Kwankanit Sae-Ung, Sujira Mukda, Piyarat Govitrapong
A deviant level of melatonin in blood circulation has been associated with the development of diabetes and with learning and memory deficiencies. Melatonin might have an important function in diabetes control; however, the mechanism of melatonin in diabetes remains unknown. The present study aimed to investigate the hyperglycemic condition induced by high-fat diet (HFD) feeding and streptozotocin (STZ) injection and to examine the effect of melatonin on adult hippocampal functions. HFD-fed and STZ-treated rats significantly increased blood glucose level...
September 13, 2016: Neurochemistry International
Itsaso Buesa, Zigor Aira, Jon Jatsu Azkue
Dopamine can influence NMDA receptor function and regulate glutamate-triggered long-term changes in synaptic strength in several regions of the CNS. In spinal cord, regulation of the threshold of synaptic plasticity may determine the proneness to undergo sensitization and hyperresponsiveness to noxious input. In the current study, we increased endogenous dopamine levels in the dorsal horn by using re-uptake inhibitor GBR 12935. During the so-induced hyperdopaminergic transmission, conditioning low-frequency (1 Hz) stimulation (LFS) to the sciatic nerve induced long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn neurons...
2016: PloS One
Jason Arsenault, Shervin Gholizadeh, Yosuke Niibori, Laura K Pacey, Sebok K Halder, Enea Koxhioni, Ayumu Konno, Hirokazu Hirai, David R Hampson
Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector-based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels...
September 7, 2016: Human Gene Therapy
Jian-Xin Jia, Cheng-Li Cui, Xu-Sheng Yan, Bai-Feng Zhang, Wei Song, Dong-Sheng Huo, He Wang, Zhan-Jun Yang
Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot...
2016: Journal of Toxicology and Environmental Health. Part A
Zhihui Xie, Kathie L Eagleson, Hsiao-Huei Wu, Pat Levitt
MET, a pleiotropic receptor tyrosine kinase implicated in autism risk, influences multiple neurodevelopmental processes. There is a knowledge gap, however, in the molecular mechanism through which MET mediates developmental events related to disorder risk. In the neocortex, MET is expressed transiently during periods of peak dendritic outgrowth and synaptogenesis, with expression enriched at developing synapses, consistent with demonstrated roles in dendritic morphogenesis, modulation of spine volume, and excitatory synapse development...
July 2016: ENeuro
Hui Wang, Rui-Yun Peng
With key roles in essential brain functions ranging from the long-term potentiation (LTP) to synaptic plasticity, the N-methyl-D-aspartic acid receptor (NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system. The role of NMDA R was first identified in synaptic plasticity and has been extensively studied. Some molecules, such as Ca(2+), postsynaptic density 95 (PSD-95), calcium/calmodulin-dependent protein kinase II (CaMK II), protein kinase A (PKA), mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), are of special importance in learning and memory...
2016: Military Medical Research
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