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Neurobiology of Disease

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https://www.readbyqxmd.com/read/28855130/pten-deletion-increases-hippocampal-granule-cell-excitability-in-male-and-female-mice
#1
Victor R Santos, Raymund Y K Pun, Salwa R Arafa, Candi L LaSarge, Shane Rowley, Shadi Khademi, Tom Bouley, Katherine D Holland, Norberto Garcia-Cairasco, Steve C Danzer
Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability...
September 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28927958/defective-gabaergic-neurotransmission-in-the-nucleus-tractus-solitarius-in-mecp2-null-mice-a-model-of-rett-syndrome
#2
Chao-Yin Chen, Jacopo Di Lucente, Yen-Chu Lin, Cheng-Chang Lien, Michael A Rogawski, Izumi Maezawa, Lee-Way Jin
Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS...
September 16, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28923597/targeting-demyelination-via-%C3%AE-secretases-promoting-sapp%C3%AE-release-to-enhance-remyelination-in-central-nervous-system
#3
Gemma Llufriu-Dabén, Alex Carrete, Elena Chierto, Jo Mailleux, Emeline Camand, Anne Simon, Tim Vanmierlo, Christiane Rose, Bernadette Allinquant, Jerome J A Hendriks, Charbel Massaad, Delphine Meffre, Mehrnaz Jafarian-Tehrani
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on α-secretase-induced sAPPα release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPα in remyelination is not known. Therefore, we investigated the remyelination potential of α-secretase-induced sAPPα release following CNS demyelination in mice...
September 15, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28923596/chemically-activated-luminopsins-allow-optogenetic-inhibition-of-distributed-nodes-in-an-epileptic-network-for-non-invasive-and-multi-site-suppression-of-seizure-activity
#4
Jack K Tung, Fu Hung Shiu, Kevin Ding, Robert E Gross
Although optogenetic techniques have proven to be invaluable for manipulating and understanding complex neural dynamics over the past decade, they still face practical and translational challenges in targeting networks involving multiple, large, or difficult-to-illuminate areas of the brain. We utilized inhibitory luminopsins to simultaneously inhibit multiple limbic structures of the rat brain in a hardware-independent and cell-type specific manner to suppress seizure activity in a rat model of epilepsy. In addition to elucidating mechanisms of seizure suppression never directly demonstrated before, this work also illustrates how precise multi-focal control of pathological circuits can be advantageous for the treatment of epilepsy, which may also be applicable to the treatment and understanding of other neurological disorders involving broad neural circuits...
September 15, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28916199/erk-and-rock-functionally-interact-in-a-signaling-network-that-is-compensationally-upregulated-in-spinal-muscular-atrophy
#5
Niko Hensel, Svetlana Baskal, Lisa Marie Walter, Hella Brinkmann, Manuela Gernert, Peter Claus
Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately...
September 12, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28890315/subthalamic-neural-entropy-is-a-feature-of-freezing-of-gait-in-freely-moving-people-with-parkinson-s-disease
#6
Judy Syrkin-Nikolau, Mandy Miller Koop, Thomas Prieto, Chioma Anidi, Muhammad Furqan Afzal, Anca Velisar, Zack Blumenfeld, Talora Martin, Megan Trager, Helen Bronte-Stewart
The goal of this study was to investigate subthalamic (STN) neural features of Freezers and Non-Freezers with Parkinson's disease (PD), while freely walking without freezing of gait (FOG) and during periods of FOG, which were better elicited during a novel turning and barrier gait task than during forward walking. METHODS: Synchronous STN local field potentials (LFPs), shank angular velocities, and ground reaction forces were measured in fourteen PD subjects (eight Freezers) off medication, OFF deep brain stimulation (DBS), using an investigative, implanted, sensing neurostimulator (Activa® PC+S, Medtronic, Inc...
September 7, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28888971/fungal-infection-in-neural-tissue-of-patients-with-amyotrophic-lateral-sclerosis
#7
Ruth Alonso, Diana Pisa, Ana M Fernández-Fernández, Alberto Rábano, Luis Carrasco
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28888970/glial-overexpression-of-dube3a-causes-seizures-and-synaptic-impairments-in-drosophila-concomitant-with-down-regulation-of-the-na-k-pump-atp%C3%AE
#8
Kevin A Hope, Mark S LeDoux, Lawrence T Reiter
Duplication 15q syndrome (Dup15q) is an autism-associated disorder co-incident with high rates of pediatric epilepsy. Additional copies of the E3 ubiquitin ligase UBE3A are thought to cause Dup15q phenotypes, yet models overexpressing UBE3A in neurons have not recapitulated the epilepsy phenotype. We show that Drosophila endogenously expresses Dube3a (fly UBE3A homolog) in glial cells and neurons, prompting an investigation into the consequences of glial Dube3a overexpression. Here we expand on previous work showing that the Na(+)/K(+) pump ATPα is a direct ubiquitin ligase substrate of Dube3a...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28888969/mtor-related-neuropathology-in-mutant-tsc2-zebrafish-phenotypic-transcriptomic-and-pharmacological-analysis
#9
Chloë Scheldeman, James D Mills, Aleksandra Siekierska, Ines Serra, Daniëlle Copmans, Anand M Iyer, Benjamin J Whalley, Jan Maes, Anna C Jansen, Lieven Lagae, Eleonora Aronica, Peter A M de Witte
Tuberous sclerosis complex (TSC) is a rare, genetic disease caused by loss-of-function mutations in either TSC1 or TSC2. Patients with TSC are neurologically characterized by the presence of abnormal brain structure, intractable epilepsy and TSC-associated neuropsychiatric disorders. Given the lack of effective long-term treatments for TSC, there is a need to gain greater insight into TSC-related pathophysiology and to identify and develop new treatments. In this work we show that homozygous tsc2(-/-) mutant zebrafish larvae, but not tsc2(+/-) and WT larvae, display enlarged brains, reduced locomotor behavior and epileptiform discharges at 7dpf...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28855129/discovery-of-novel-stroke-responsive-lncrnas-in-the-mouse-cortex-using-genome-wide-rna-seq
#10
Sunil Bhattarai, Fabrizio Pontarelli, Emily Prendergast, Ashutosh Dharap
Long noncoding RNAs (lncRNAs) play major roles in regulating gene expression in mammals, but are poorly understood in ischemic stroke. Using a mouse model of transient focal ischemia, we applied RNA-seq to evaluate for the first time the unbiased, genome-wide expression of lncRNAs as a function of reperfusion time in the cerebral cortex. Focal ischemia was induced in adult male C57BL/6 mice followed by reperfusion for 6, 12 or 24h. Total RNA from ipsilateral cortices was used for Illumina sequencing and reads were mapped to the mouse reference genome (GRCm38)...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28887151/altered-synaptobrevin-ii-trafficking-in-neurons-expressing-a-synaptophysin-mutation-associated-with-a-severe-neurodevelopmental-disorder
#11
Callista B Harper, Grazia M S Mancini, Marjon van Slegtenhorst, Michael A Cousin
Following exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I)...
September 5, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28870844/inhibitory-synapse-deficits-caused-by-familial-%C3%AE-1-gabaa-receptor-mutations-in-epilepsy
#12
Xiumin Chen, Nela Durisic, Joseph W Lynch, Angelo Keramidas
Epilepsy is a spectrum of neurological disorders with many causal factors. The GABA type-A receptor (GABAAR) is a major genetic target for heritable human epilepsies. Here we examine the functional effects of three epilepsy-causing mutations to the α1 subunit (α1(T10'I), α1(D192N) and α1(A295D)) on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic GABAAR isoform, α1β2γ2L. We employed a neuron - HEK293 cell heterosynapse preparation to record IPSCs mediated by mutant-containing GABAARs in isolation from other GABAAR isoforms...
September 1, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28865749/differential-deregulation-of-ngf-and-bdnf-neurotrophins-in-a-transgenic-rat-model-of-alzheimer-s-disease
#13
M Florencia Iulita, M Beatriz Bistué Millón, Rowan Pentz, Lisi Flores Aguilar, Sonia Do Carmo, Simon Allard, Bernadeta Michalski, Edward N Wilson, Adriana Ducatenzeiler, Martin A Bruno, Margaret Fahnestock, A Claudio Cuello
Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits...
September 1, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28860089/canine-neuronal-ceroid-lipofuscinoses-promising-models-for-preclinical-testing-of-therapeutic-interventions
#14
REVIEW
Martin L Katz, Eline Rustad, Grace O Robinson, Rebecca E H Whiting, Jeffrey T Student, Joan R Coates, Kristina Narfstrom
The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from...
August 30, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28860088/tau-and-amyloid-related-pathologies-in-the-entorhinal-cortex-have-divergent-effects-in-the-hippocampal-circuit
#15
S L Angulo, R Orman, S A Neymotin, L Liu, L Buitrago, E Cepeda-Prado, D Stefanov, W W Lytton, M Stewart, S A Small, K E Duff, H Moreno
The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability...
August 30, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28860087/pro-excitatory-alterations-in-sodium-channel-activity-facilitate-subiculum-neuron-hyperexcitability-in-temporal-lobe-epilepsy
#16
Bryan S Barker, Aradhya Nigam, Matteo Ottolini, Ronald P Gaykema, Nicholas J Hargus, Manoj K Patel
Temporal lobe epilepsy (TLE) is a common form of adult epilepsy involving the limbic structures of the temporal lobe. Subiculum neurons act to provide a major output from the hippocampus and consist of a large population of endogenously bursting excitatory neurons. In TLE, subiculum neurons are largely spared, become hyperexcitable and show spontaneous epileptiform activity. The basis for this hyperexcitability is unclear, but is likely to involve alterations in the expression levels and function of various ion channels...
August 30, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28847567/continues-administration-of-nano-pso-significantly-increased-survival-of-genetic-cjd-mice
#17
Orli Binyamin, Guy Keller, Kati Frid, Liraz Larush, Shlomo Magdassi, Ruth Gabizon
We have shown previously that Nano-PSO, a nanodroplet formulation of pomegranate seed oil, delayed progression of neurodegeneration signs when administered for a designated period of time to TgMHu2ME199K mice, modeling for genetic prion disease. In the present work, we treated these mice with a self-emulsion formulation of Nano-PSO or a parallel Soybean oil formulation from their day of birth until a terminal disease stage. We found that long term Nano-PSO administration resulted in increased survival of TgMHu2ME199K lines by several months...
August 25, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28844789/protocadherin-10-alters-%C3%AE-oscillations-amino-acid-levels-and-their-coupling-baclofen-partially-restores-these-oscillatory-deficits
#18
Russell G Port, Christopher Gajewski, Elizabeth Krizman, Holly C Dow, Shinji Hirano, Edward S Brodkin, Gregory C Carlson, Michael B Robinson, Timothy P L Roberts, Steven J Siegel
Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10(+/-)) has been investigated as a proxy for ASD. Male Pcdh10(+/-) mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD...
August 24, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28844788/spatiotemporal-resolution-of-spinal-meningeal-and-parenchymal-inflammation-during-experimental-autoimmune-encephalomyelitis
#19
Bandana Shrestha, Xi Jiang, Shujun Ge, Debayon Paul, Peter Chianchiano, Joel S Pachter
Experimental autoimmune encephalomyelitis (EAE) induced by active immunization of C57BL/6 mice with peptide from myelin oligodendrocyte protein (MOG35-55), is a neuroinflammatory, demyelinating disease widely recognized as an animal model of multiple sclerosis (MS). Typically, EAE presents with an ascending course of paralysis, and inflammation that is predominantly localized to the spinal cord. Recent studies have further indicated that inflammation - in both MS and EAE - might initiate within the meninges and propagate from there to the underlying parenchyma...
August 24, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28830843/inhibition-of-tpa-induced-hemorrhagic-transformation-involves-adenosine-a2b-receptor-activation-after-cerebral-ischemia
#20
Qiang Li, Xiaoning Han, Xi Lan, Xiaohua Hong, Qian Li, Yufeng Gao, Tianqi Luo, Qingwu Yang, Raymond C Koehler, Yu Zhai, Jinyuan Zhou, Jian Wang
Tissue plasminogen activator (tPA) is administered after ischemic stroke to dissolve intravascular clots, but its use can lead to hemorrhagic transformation (HT). Therapeutic strategies to reduce hemorrhagic complications of tPA might be of benefit for stroke patients. Adenosine A2b receptor (A2bR) plays pivotal roles in regulating vascular protection in peripheral organs. This study explored whether A2bR agonist BAY 60-6583 reduces hemorrhage risk after tPA usage. Using a rat transient middle cerebral artery occlusion model, we showed that mRNA and protein expression of A2bR increased to a greater extent after ischemia-reperfusion than did expression of the other three adenosine receptors (A1, A2a, and A3)...
August 19, 2017: Neurobiology of Disease
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