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      Defective glutamate and K + clearance by cortical astrocytes in familial hemiplegic migraine type 2


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          Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 2: FHM2) is caused by loss‐of‐function mutations in α 2 Na +,K + ATPase (α 2 NKA), an isoform almost exclusively expressed in astrocytes in adult brain. Cortical spreading depression ( CSD), the phenomenon that underlies migraine aura and activates migraine headache mechanisms, is facilitated in heterozygous FHM2‐knockin mice with reduced expression of α 2 NKA. The mechanisms underlying an increased susceptibility to CSD in FHM2 are unknown. Here, we show reduced rates of glutamate and K + clearance by cortical astrocytes during neuronal activity and reduced density of GLT‐1a glutamate transporters in cortical perisynaptic astrocytic processes in heterozygous FHM2‐knockin mice, demonstrating key physiological roles of α 2 NKA and supporting tight coupling with GLT‐1a. Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters in wild‐type mice, we obtain evidence that defective glutamate clearance can account for most of the facilitation of CSD initiation in FHM2‐knockin mice, pointing to excessive glutamatergic transmission as a key mechanism underlying the vulnerability to CSD ignition in migraine.

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          Most cited references88

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          Glutamate uptake.

          Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.
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            Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

            Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.
              • Record: found
              • Abstract: found
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              Localization of neuronal and glial glutamate transporters.

              The cellular and subcellular distributions of the glutamate transporter subtypes EAAC1, GLT-1, and GLAST in the rat CNS were demonstrated using anti-peptide antibodies that recognize the C-terminal domains of each transporter. On immunoblots, the antibodies specifically recognize proteins of 65-73 kDa in total brain homogenates. Immunocytochemistry shows that glutamate transporter subtypes are distributed differentially within neurons and astroglia. EAAC1 is specific for certain neurons, such as large pyramidal cortical neurons and Purkinje cells, but does not appear to be selective for glutamatergic neurons. GLT-1 is localized only to astroglia. GLAST is found in both neurons and astroglia. The regional localizations are unique to each transporter subtype. EAAC1 is highly enriched in the cortex, hippocampus, and caudate-putamen and is confined to pre- and postsynaptic elements. GLT-1 is distributed in astrocytes throughout the brain and spinal cord. GLAST is most abundant in Bergmann glia in the cerebellar molecular layer brain, but is also present in the cortex, hippocampus, and deep cerebellar nuclei.

                Author and article information

                EMBO Mol Med
                EMBO Mol Med
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                27 June 2016
                August 2016
                : 8
                : 8 ( doiID: 10.1002/emmm.v8.8 )
                : 967-986
                [ 1 ] Department of Biomedical SciencesUniversity of Padova PadovaItaly
                [ 2 ] Department of Experimental and Clinical MedicineUniversità Politecnica delle Marche AnconaItaly
                [ 3 ] Center for Neurobiology of AgingINRCA IRCCS AnconaItaly
                [ 4 ] Institute of Pharmacology and ToxicologyUniversity of Zurich ZürichSwitzerland
                [ 5 ]Vita‐Salute San Raffaele University and San Raffaele Scientific Institute MilanoItaly
                [ 6 ] Fondazione di Medicina MolecolareUniversità Politecnica delle Marche AnconaItaly
                [ 7 ]CNR Institute of Neuroscience PadovaItaly
                Author notes
                [*] [* ]Corresponding author. Tel: +39 049 827 6052; E‐mail: daniela.pietrobon@ 123456unipd.it

                These authors contributed equally to the work

                Author information
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 15 October 2015
                : 27 May 2016
                : 31 May 2016
                Page count
                Pages: 20
                Funded by: Fondazione Telethon
                Award ID: GGP14234
                Funded by: Italian Ministry of University and Research
                Award ID: PRIN2010
                Funded by: University of Padova
                Award ID: Progetto Ateneo 2012
                Funded by: INRCA IRCCS
                Funded by: Università Politecnica delle Marche
                Research Article
                Research Articles
                Custom metadata
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:01.08.2016

                Molecular medicine
                ceftriaxone,glutamate transporter,migraine,na+,k+atpase,spreading depression,neuroscience


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