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https://www.readbyqxmd.com/read/29651456/systematic-reconstruction-of-autism-biology-from-massive-genetic-mutation-profiles
#1
Weijun Luo, Chaolin Zhang, Yong-Hui Jiang, Cory R Brouwer
Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module)...
April 2018: Science Advances
https://www.readbyqxmd.com/read/29627342/blockade-of-%C3%AE-2-adrenergic-or-metabotropic-glutamate-receptors-induces-glutamate-release-in-the-locus-coeruleus-to-activate-descending-inhibition-in-rats-with-chronic-neuropathic-hypersensitivity
#2
Ken-Ichiro Hayashida, Masafumi Kimuram, James C Eisenach
Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the α2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-α-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or α2-adrenoceptors in the spinal cord, but not in normal animals...
April 5, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29625424/mglu-receptors-in-the-treatment-of-parkinson-s-disease-and-l-dopa-induced-dyskinesia
#3
REVIEW
Irene Sebastianutto, Maria Angela Cenci
Parkinson's disease (PD) is a neurodegenerative disorder characterized by typical motor features that result from dopamine (DA) depletion in the striatum. DA replacement therapy with L-DOPA is the most efficacious symptomatic treatment, but causes complications that limit its utility, in particular, L-DOPA-induced dyskinesia (LID). LID is primarily caused by pre-synaptic and post-synaptic changes in DA neurotransmission, although it also depends on altered glutamatergic transmission at several nodes of the cortico-basal ganglia-thalamocortical network...
April 3, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29617377/inositol-1-4-5-trisphosphate-3-kinase-a-overexpressed-in-mouse-forebrain-modulates-synaptic-transmission-and-mglur-ltd-of-ca1-pyramidal-neurons
#4
Byungil Choi, Hyun Woo Lee, Seojung Mo, Jin Yong Kim, Hyun Wook Kim, Im Joo Rhyu, Eunhwa Hong, Yeon Kyung Lee, June-Seek Choi, Chong-Hyun Kim, Hyun Kim
Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus...
2018: PloS One
https://www.readbyqxmd.com/read/29614089/hippocampal-protein-kinase-d1-is-necessary-for-dhpg-induced-learning-and-memory-impairments-in-rats
#5
Wei Wang, Florian Duclot, Bradley R Groveman, Nicole Carrier, Haifa Qiao, Xiao-Qian Fang, Hui Wang, Wenkuan Xin, Xing-Hong Jiang, Michael W Salter, Xin-Sheng Ding, Mohamed Kabbaj, Xian-Min Yu
BACKGROUND: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs...
2018: PloS One
https://www.readbyqxmd.com/read/29605730/metabotropic-glutamate-receptors-targets-for-neuroprotective-therapies-in-parkinson-disease
#6
REVIEW
Gunasingh J Masilamoni, Yoland Smith
Metabotropic glutamate receptors (mGluRs) are heavily expressed throughout the basal ganglia (BG), where they modulate neuronal excitability, transmitter release and long term synaptic plasticity. Therefore, targeting specific mGluR subtypes by means of selective drugs could be a possible strategy for restoring normal synaptic function and neuronal activity of the BG in Parkinson disease (PD). Preclinical studies have revealed that specific mGluR subtypes mediate significant neuroprotective effects that reduce toxin-induced midbrain dopaminergic neuronal death in animal models of PD...
March 29, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29605484/amn082-a-metabotropic-glutamate-receptor-type-7-allosteric-agonist-in-the-nac-facilitates-extinction-and-inhibits-the-reinstatement-of-morphine-induced-conditioned-place-preference-in-male-rats
#7
Mahsaneh Vatankhah, Abdolrahman Sarihi, Alireza Komaki, Siamak Shahidi, Abbas Haghparast
Nucleus accumbens (NAc) plays plays a primary role in opioid reward. The actions of glutamate (which is the most extensive excitatory neurotransmitter in the mammalian central nervous system) are mediated through the activation of the ionotropic and metabotropic glutamate receptors (mGluRs). Previous studies have shown the extensive distributions of the different types of mGluRs, including mGluR7, in regions that are involved in opioid reward, such as NAc. In this study, CPP was used to investigate the effect of mGluR7 on the extinction period, and the reinstatement of morphine...
March 29, 2018: Brain Research Bulletin
https://www.readbyqxmd.com/read/29593596/neural-dynamics-of-autistic-repetitive-behaviors-and-fragile-x-syndrome-basal-ganglia-movement-gating-and-mglur-modulated-adaptively-timed-learning
#8
Stephen Grossberg, Devika Kishnan
This article develops the iSTART neural model that proposes how specific imbalances in cognitive, emotional, timing, and motor processes that involve brain regions like prefrontal cortex, temporal cortex, amygdala, hypothalamus, hippocampus, and cerebellum may interact together to cause behavioral symptoms of autism. These imbalances include underaroused emotional depression in the amygdala/hypothalamus, learning of hyperspecific recognition categories that help to cause narrowly focused attention in temporal and prefrontal cortices, and breakdowns of adaptively timed motivated attention and motor circuits in the hippocampus and cerebellum...
2018: Frontiers in Psychology
https://www.readbyqxmd.com/read/29588465/mef2a-regulates-mglur-dependent-ampa-receptor-trafficking-independently-of-arc-arg3-1
#9
Ruth E Carmichael, Kevin A Wilkinson, Tim J Craig, Michael C Ashby, Jeremy M Henley
Differential trafficking of AMPA receptors (AMPARs) to and from the postsynaptic membrane is a key determinant of the strength of excitatory neurotransmission, and is thought to underlie learning and memory. The transcription factor MEF2 is a negative regulator of memory in vivo, in part by regulating trafficking of the AMPAR subunit GluA2, but the molecular mechanisms behind this have not been established. Here we show, via knockdown of endogenous MEF2A in primary neuronal culture, that MEF2A is specifically required for Group I metabotropic glutamate receptor (mGluR)-mediated GluA2 internalisation, but does not regulate AMPAR expression or trafficking under basal conditions...
March 27, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29572827/activity-dependent-synaptic-integration-and-modulation-of-bilateral-excitatory-inputs-in-an-auditory-coincidence-detection-circuit
#10
Yong Lu, Yuwei Liu, Rebecca J Curry
Neurons in the avian nucleus laminaris (NL) receive bilateral excitatory inputs from the cochlear nucleus magnocellularis, via morphologically symmetrical dorsal (ipsilateral) and ventral (contralateral) dendrites. Using in vitro whole-cell patch recordings in chicken brainstem slices, we investigated synaptic integration and modulation of the bilateral inputs to NL under normal and hearing deprivation conditions. We found that the two excitatory inputs onto single NL neurons were nearly completely segregated, and integration of the two inputs was linear for EPSPs...
March 23, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29564482/group-ii-metabotropic-glutamate-receptor-agonist-prodrugs-ly2979165-and-ly2140023-attenuate-the-functional-imaging-response-to-ketamine-in-healthy-subjects
#11
Mitul A Mehta, Anne Schmechtig, Vasileia Kotoula, Juliet McColm, Kimberley Jackson, Claire Brittain, Sitra Tauscher-Wisniewski, Bruce J Kinon, Paul D Morrison, Thomas Pollak, Timothy Mant, Steven C R Williams, Adam J Schwarz
BACKGROUND: Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-D-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system...
March 21, 2018: Psychopharmacology
https://www.readbyqxmd.com/read/29545119/regulation-of-ampa-receptor-trafficking-and-exit-from-the-endoplasmic-reticulum
#12
REVIEW
Joseph E Pick, Edward B Ziff
A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent on synaptic plasticity. It is now appreciated that for excitatory synapses, a significant part of synaptic plasticity depends upon changes in the post synaptic response to glutamate released from nerve terminals. Modification of the post synaptic response depends, in turn, on changes in the abundances of AMPA receptors in the post synaptic membrane...
March 12, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29535613/trpc1-channels-are-expressed-in-pyramidal-neurons-and-in-a-subset-of-somatostatin-interneurons-in-the-rat-neocortex
#13
Juan R Martinez-Galan, Ana Verdejo, Elena Caminos
Disturbances in calcium homeostasis due to canonical transient receptor potential (TRPC) and/or store-operated calcium (SOC) channels can play a key role in a large number of brain disorders. TRPC channels are plasma membrane cation channels included in the transient receptor potential (TRP) superfamily. The most widely distributed member of the TRPC subfamily in the brain is TRPC1, which is frequently linked to group I metabotropic glutamate receptors (mGluRs) and to the components of SOC channels. Proposing TRPC/SOC channels as a therapeutic target in neurological diseases previously requires a detailed knowledge of the distribution of such molecules in the brain...
2018: Frontiers in Neuroanatomy
https://www.readbyqxmd.com/read/29524437/metabotropic-glutamate-receptor-modulation-of-dopamine-release-in-the-nucleus-accumbens-shell-is-unaffected-by-phencyclidine-pretreatment-in-vitro-assessment-using-fast-scan-cyclic-voltammetry-rat-brain-slices
#14
Ishan Gupta, Andrew M J Young
The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release...
March 7, 2018: Brain Research
https://www.readbyqxmd.com/read/29513763/computational-modeling-of-opioid-induced-synaptic-plasticity-in-hippocampus
#15
Mehdi Borjkhani, Fariba Bahrami, Mahyar Janahmadi
According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP...
2018: PloS One
https://www.readbyqxmd.com/read/29505763/interactions-between-estrogen-receptors-and-metabotropic-glutamate-receptors-and-their-impact-on-drug-addiction-in-females
#16
REVIEW
Katherine R Tonn Eisinger, Kellie S Gross, Brian P Head, Paul G Mermelstein
Estrogen receptors α and β (ERα and ERβ) have a unique relationship with metabotropic glutamate receptors (mGluRs) in the female rodent brain such that estradiol is able to recruit intracellular G-protein signaling cascades to influence neuronal physiology, structure, and ultimately behavior. While this association between ERs and mGluRs exists in many cell types and brain regions, its effects are perhaps most striking in the nucleus accumbens (NAc). This review will discuss the original characterization of ER/mGluR signaling and how estradiol activity in the NAc confers increased sensitivity to drugs of abuse in females through this mechanism...
March 2, 2018: Hormones and Behavior
https://www.readbyqxmd.com/read/29481317/a-postmortem-analysis-of-nmda-ionotropic-and-group-1-metabotropic-glutamate-receptors-in-the-nucleus-accumbens-in-schizophrenia
#17
Jeremy S Lum, Samuel J Millard, Xu-Feng Huang, Lezanne Ooi, Kelly A Newell
BACKGROUND: The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort. METHODS: We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the N -methyl-D-aspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms)...
March 2018: Journal of Psychiatry & Neuroscience: JPN
https://www.readbyqxmd.com/read/29455105/shedding-light-on-metabotropic-glutamate-receptors-using-optogenetics-and-photopharmacology
#18
REVIEW
Cyril Goudet, Xavier Rovira, Amadeu Llebaria
Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors activated by glutamate, the main excitatory neurotransmitter of the mammalian central nervous system. These receptors are considered as potential therapeutic targets in many neurological diseases but a better understanding of their complex molecular dynamics and of their role in the normal and pathological functioning of the brain is still required. Manipulating mGluRs with high spatial and temporal precision holds great promise for deciphering their physiological and pathological functions...
February 15, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29421611/gpr30-activation-improves-memory-and-facilitates-dhpg-induced-ltd-in-the-hippocampal-ca3-of-middle-aged-mice
#19
Wen Xu, Jian Cao, Yan Zhou, Lina Wang, Guoqi Zhu
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15...
February 5, 2018: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/29407217/the-role-of-19s-proteasome-associated-deubiquitinases-in-activity-dependent-hippocampal-synaptic-plasticity
#20
Di Yun, Yinghan Zhuang, Michael R Kreutz, Thomas Behnisch
Posttranslational modification and degradation of proteins by the ubiquitin-proteasome system (UPS) is crucial to synaptic transmission. It is well established that 19S proteasome associated deubiquitinases (DUBs) reverse the process of ubiquitination by removing ubiquitin from their substrates. However, their potential contribution to hippocampal synaptic plasticity has not been addressed in detail. Here, we report that inhibition of the 19S proteasome associated DUBs, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14) by b-AP15 results in an accumulation of polyubiquitinated proteins and a reduction of monomeric ubiquitin without overt effects on 26S proteasome activity...
January 30, 2018: Neuropharmacology
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