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Glutamatergic dysregulation

Alina Kurolap, Anja Armbruster, Tova Hershkovitz, Katharina Hauf, Adi Mory, Tamar Paperna, Ewald Hannappel, Galit Tal, Yusif Nijem, Ella Sella, Muhammad Mahajnah, Anat Ilivitzki, Dov Hershkovitz, Nina Ekhilevitch, Hanna Mandel, Volker Eulenburg, Hagit N Baris
Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure...
October 18, 2016: American Journal of Human Genetics
Daniel García-Pérez, Szilamer Ferenczi, Krisztina J Kovács, M Luisa Laorden, M Victoria Milanés, Cristina Núñez
Drug-withdrawal aversive memories generate a motivational state leading to compulsive drug taking, with plasticity changes in the basolateral amygdala (BLA) being essential in aversive motivational learning. The conditioned-place aversion (CPA) paradigm allows for measuring the negative affective component of drug withdrawal. First, CPA triggers association between negative affective consequences of withdrawal with context (memory consolidation). Afterwards, when the animals are re-exposed to the paired environment, they avoid it due to the association between the context and aversive memories (memory retrieval)...
September 28, 2016: Psychoneuroendocrinology
Oliver D Howes, Robert McCutcheon, Michael J Owen, Robin M Murray
The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes...
August 6, 2016: Biological Psychiatry
Omar Ouachikh, Carine Chassain, Guilhem Pagès, Franck Durif, Aziz Hafidi
Dopamine dysregulation syndrome (DDS) has been attributed to both dopamine replacement therapies (DRT) and the mesencephalic dopaminergic lesion. The DRT reinforcement effect is due to its action on the reward system, particularly on the nucleus accumbens (NAc). This nucleus receives two major projections, a glutamatergic from the prefrontal cortex and a dopaminergic from the posterior ventral tegmental area (pVTA). The latter modulate the former within the NAc. pVTA has been demonstrated to be implicated in the motivational effect of bromocriptine (dopamine 2 receptor (D2R) agonist) in bilateral pVTA-lesioned animals...
September 13, 2016: Behavioural Brain Research
Sara M F Turner, Darin J Falk, Barry J Byrne, David D Fuller
Pompe disease, caused by deficiency of acid alpha-glucosidase (GAA), leads to widespread glycogen accumulation and profound neuromuscular impairments. There has been controversy, however, regarding the role of central nervous system pathology in Pompe motor dysfunction. We hypothesized that absence of GAA protein causes progressive activation of neuropathological signaling, including pathways associated with cell death. To test this hypothesis, genomic data (Affymetrix Mouse Gene Array 2.0ST) from the mid-cervical spinal cord in 6- and 16-mo old Pompe (Gaa(-/-)) were evaluated (Broad Institute Molecular Signature Database), along with spinal cord histology...
September 9, 2016: Physiological Genomics
Lucia Carboni, Thanh-Phuong Nguyen, Laura Caberlotto
PURPOSE: The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular underpinnings of depressive-like behaviours with an unbiased approach. The objective of the study is to integrate the results of these proteomic studies in depression models to shed light on the most relevant molecular pathways involved in the disease. EXPERIMENTAL DESIGN: Network analysis is performed integrating preexisting proteomic data from rodent models of depression...
September 10, 2016: Proteomics. Clinical Applications
José Luiz de Brito Alves, Jéssica Maricelly Deodato de Oliveira, Dioginis José Soares Ferreira, Monique Assis V de Barros, Viviane Oliveira Nogueira, Débora Santos Alves, Hubert Vidal, Carol Gois Leandro, Cláudia Jacques Lagranha, Luciano Pirola, João Henrique da Costa-Silva
Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension...
September 9, 2016: Clinical and Experimental Pharmacology & Physiology
Haruko Nakamura, Naoya Yamashita, Ayuko Kimura, Yayoi Kimura, Hisashi Hirano, Hiroko Makihara, Yuko Kawamoto, Aoi Jitsuki-Takahashi, Kumiko Yonezaki, Kenkichi Takase, Tomoyuki Miyazaki, Fumio Nakamura, Fumiaki Tanaka, Yoshio Goshima
Collapsin response mediator protein 2 (CRMP2) plays a key role in axon guidance, dendritic morphogenesis and cell polarization. CRMP2 is implicated in various neurological and psychiatric disorders. However, in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2(-/-) ) mice and examined their behavioral phenotypes. During 24-h home cage monitoring, the activity level during the dark phase of crmp2(-/-) mice was significantly higher than that of wild-type (WT) mice. Moreover, the time during the open arm of an elevated plus maze was longer for crmp2(-/-) mice than for WT mice...
October 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Idrish Ali, Stephanie Boets, Pieter Janssens, Annemie Van Eetveldt, Halima Amhaoul, Xavier Langlois, Stefanie Dedeurwaerdere
Dysregulation in the glutamatergic function is considered a major contributor to hyperexcitatory neuronal networks in mesial temporal lobe epilepsy (MTLE). Studies in animal models of MTLE have shown positive outcomes of augmenting group 2-metabotropic receptor functions that can regulate neuronal excitability from extrasynaptic locations. To assist in efficient translation of these findings to the clinical settings, we aimed to characterise the expression of mGluR2/3 receptors in the brain areas relevant to MTLE...
August 13, 2016: Epilepsy Research
Viviana Filpa, Elisabetta Moro, Marina Protasoni, Francesca Crema, Gianmario Frigo, Cristina Giaroni
Several studies have been carried out in the last 30 years in the attempt to clarify the possible role of glutamate as a neurotransmitter/neuromodulator in the gastrointestinal tract. Such effort has provided immunohistochemical, biomolecular and functional data suggesting that the entire glutamatergic neurotransmitter machinery is present in the complex circuitries of the enteric nervous system (ENS), which participates to the local coordination of gastrointestinal functions. Glutamate is also involved in the regulation of the brain-gut axis, a bi-directional connection pathway between the central nervous system (CNS) and the gut...
December 2016: Neuropharmacology
C Cruceanu, J P Lopez, W-T Tsai, G Turecki
No abstract text is available yet for this article.
August 23, 2016: Molecular Psychiatry
Emma M Perkins, Daumante Suminaite, Yvonne L Clarkson, Sin Kwan Lee, Alastair R Lyndon, Jeffrey D Rothstein, David Ja Wyllie, Kohichi Tanaka, Mandy Jackson
Clinical phenotypes of spinocerebellar ataxia type-5 (SCA5) and spectrin-associated autosomal recessive cerebellar ataxia type-1 (SPARCA1) are mirrored in mice lacking β-III spectrin (β-III(-/-)). One function of β-III spectrin is the stabilisation of the Purkinje cell-specific glutamate transporter EAAT4 at the plasma membrane. In β-III(-/-) mice EAAT4 levels are reduced from an early age. In contrast levels of the predominant cerebellar glutamate transporter GLAST, expressed in Bergmann glia, only fall progressively from 3 months onwards...
August 15, 2016: Human Molecular Genetics
Kara R Vogel, Garrett R Ainslie, K Michael Gibson
Recent studies have identified a role for supraphysiological gamma-aminobutyric acid (GABA) in the regulation of mechanistic target of rapamycin (mTOR), a protein kinase with pleiotropic roles in cellular development and homeostasis, including integration of growth factors and nutrient sensing and synaptic input in neurons (Lakhani et al. 2014; Vogel et al. 2015). Aldehyde dehydrogenase 5a1-deficient (aldh5a1 (-/-) ) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA that disrupts mitophagy and increases mitochondria number with enhanced oxidant stress...
November 2016: Journal of Inherited Metabolic Disease
Ya Bin Wei, Philippe A Melas, J Carlos Villaescusa, Jia Jia Liu, Ning Xu, Søren Hofman Christiansen, Heidi Elbrønd-Bek, David Paul Drucker Woldbye, Gregers Wegener, Aleksander A Mathé, Catharina Lavebratt
BACKGROUND: MicroRNAs (miRNAs) are small regulatory molecules that cause translational repression by base pairing with target mRNAs. Cumulative evidence suggests that changes in miRNA expression may in part underlie the pathophysiology and treatment of neuropsychiatric disorders, including major depressive disorder (MDD). METHODS: A miRNA expression assay that can simultaneously detect 423 rat miRNAs (miRBase v.17) was used to profile the prefrontal cortex (PFC) of a genetic rat model of MDD (the Flinders Sensitive Line [FSL]) and the controls, the Flinders Resistant Line (FRL)...
September 30, 2016: International Journal of Neuropsychopharmacology
Carie R Boychuk, Bret N Smith
The role of central regulatory circuits in modulating diabetes-associated glucose dysregulation has only recently been under rigorous investigation. One brain region of interest is the dorsal motor nucleus of the vagus (DMV), which contains preganglionic parasympathetic motor neurons that regulate subdiaphragmatic visceral function. Previous research has demonstrated that glutamatergic and GABAergic neurotransmission are independently remodeled after chronic hyperglycemia/hypoinsulinemia. However, glutamatergic circuitry within the dorsal brain stem impinges on GABAergic regulation of the DMV...
September 1, 2016: Journal of Neurophysiology
Venugopalan D Nair, Yongchao Ge
Molecular adaptations in the striatum mediated by dopamine (DA) denervation and/or levodopa (L-dopa) treatments have been implicated in the motor deficits found in Parkinson's disease (PD). Alterations in inflammatory response mechanisms and glutamatergic neurotransmission are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. Small non-coding microRNAs (miRNAs) influence numerous biological processes including the development and maintenance of striatal neurons by regulating gene expression post-transcriptionally...
August 26, 2016: Neuroscience Letters
Zhi Zhang, Bassam Bassam, Ajit G Thomas, Monica Williams, Jinhuan Liu, Elizabeth Nance, Camilo Rojas, Barbara S Slusher, Sujatha Kannan
Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial 'activation' and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain...
October 2016: Neurobiology of Disease
P Malaspina, J-B Roullet, P L Pearl, G R Ainslie, K R Vogel, K M Gibson
Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected...
October 2016: Neurochemistry International
Alessia De Felice, Anita Greco, Gemma Calamandrei, Luisa Minghetti
BACKGROUND: Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. Oxidative stress and dysregulated immune responses are implicated in both organophosphate neurodevelopmental effects and ASD etiopathogenesis...
2016: Journal of Neuroinflammation
Michele Curcio, Ivan L Salazar, Miranda Mele, Lorella M T Canzoniero, Carlos B Duarte
The excessive extracellular accumulation of glutamate in the ischemic brain leads to an overactivation of glutamate receptors with consequent excitotoxic neuronal death. Neuronal demise is largely due to a sustained activation of NMDA receptors for glutamate, with a consequent increase in the intracellular Ca(2+) concentration and activation of calcium- dependent mechanisms. Calpains are a group of Ca(2+)-dependent proteases that truncate specific proteins, and some of the cleavage products remain in the cell, although with a distinct function...
August 2016: Progress in Neurobiology
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