title: Sprouty2 and -4 hypomorphism promotes neuronal survival and astrocytosis in a mouse model of kainic acid induced neuronal damage.
abstract: Sprouty (Spry) proteins play a key role as negative feedback inhibitors of the Ras/Raf/MAPK/ERK pathway downstream of various receptor tyrosine kinases. Among the four Sprouty isoforms, Spry2 and Spry4 are expressed in the hippocampus. In this study, possible effects of Spry2 and Spry4 hypomorphism on neurodegeneration and seizure thresholds in a mouse model of epileptogenesis was analyzed. The Spry2/4 hypomorphs exhibited stronger ERK activation which was limited to the CA3 pyramidal cell layer and to the hilar region. The seizure threshold of Spry2/4(+/-) mice was significantly reduced at naive state but no difference to wildtype mice was observed 1 month following KA treatment. Histomorphological analysis revealed that dentate granule cell dispersion (GCD) was diminished in Spry2/4(+/-) mice in the subchronic phase after KA injection. Neuronal degeneration was reduced in CA1 and CA3 principal neuron layers as well as in scattered neurons of the contralateral CA1 and hilar regions. Moreover, Spry2/4 reduction resulted in enhanced survival of somatostatin and neuropeptide Y expressing interneurons. GFAP staining intensity and number of reactive astrocytes markedly increased in lesioned areas of Spry2/4(+/-) mice as compared with wildtype mice. Taken together, although the seizure threshold is reduced in naive Spry2/4(+/-) mice, neurodegeneration and GCD is mitigated following KA induced hippocampal lesions, identifying Spry proteins as possible pharmacological targets in brain injuries resulting in neurodegeneration. The present data are consistent with the established functions of the ERK pathway in astrocyte proliferation as well as protection from neuronal cell death and suggest a novel role of Spry proteins in the migration of differentiated neurons.
authors.affiliation: Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Sitthisak
authors.initials: S
authors.lastname: Thongrong
authors.affiliation: Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hausott
authors.affiliation: Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Letizia
authors.initials: L
authors.lastname: Marvaldi
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Innsbruck, 6020, Austria.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Agostinho
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Innsbruck, 6020, Austria.
authors.forename: Luca
authors.initials: L
authors.lastname: Zangrandi
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Innsbruck, 6020, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Burtscher
authors.affiliation: Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fogli
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, Innsbruck, 6020, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Division of Neuroanatomy, Department of Anatomy Histology and Embryology, Medical University, Innsbruck, 6020, Innsbruck, Austria.
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010433:Pentylenetetrazole / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C499037:Spry4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D007608:Kainic Acid; D010433:Pentylenetetrazole
keywords: ERK; Sprouty; gliosis; granule cell dispersion; hippocampus; neurodegeneration