title: A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex.
abstract: Polysialic acid (polySia) is a unique glycan modification of the neural cell adhesion molecule NCAM and a major determinant of brain development. Polysialylation of NCAM is implemented by the two polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4. Dysregulation of the polySia-NCAM system and variation in ST8SIA2 has been linked to schizophrenia and other psychiatric disorders. Here, we show reduced interneuron densities in the medial prefrontal cortex (mPFC) of mice with either partial or complete loss of polySia synthesizing capacity by ablation of St8sia2, St8sia4, or both. Cells positive for parvalbumin and perineuronal nets as well as somatostatin-positive cells were reduced in the mPFC of all polyST-deficient lines, whereas calretinin-positive cells and the parvalbumin-negative fraction of calbindin-positive cells were unaffected. Reduced interneuron numbers were corroborated by analyzing polyST-deficient GAD67-GFP knock-in mice. The accumulation of precursors in the ganglionic eminences and reduced numbers of tangentially migrating interneurons in the pallium were observed in polyST-deficient embryos. Removal of polySia by endosialidase treatment of organotypic slice cultures led to decreased entry of GAD67-GFP-positive interneurons from the ganglionic eminences into the pallium. Moreover, the acute loss of polySia caused significant reductions in interneuron velocity and leading process length. Thus, attenuation of polySia interferes with the developmental migration of cortical interneurons and causes pathological changes in specific interneuron subtypes. This provides a possible link between genetic variation in polyST genes, neurodevelopmental alterations and interneuron dysfunction in neuropsychiatric disease.
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Center for Systems Neuroscience Hannover (ZSN), 30559 Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kröcher
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Röckle
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Diederichs
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Weinhold
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Burkhardt
authors.affiliation: Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and CREST, 3-39-22 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Center for Systems Neuroscience Hannover (ZSN), 30559 Hannover, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Center for Systems Neuroscience Hannover (ZSN), 30559 Hannover, Germany hildebrandt.herbert@mh-hannover.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D017209:Apoptosis; D064026:Calbindins / Q000378:metabolism; D002465:Cell Movement; D014644:Genetic Variation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D017397:Prefrontal Cortex / Q000166:cytology*; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics; D013004:Somatostatin / Q000378:metabolism
chemical_list: D064026:Calbindins; D019006:Neural Cell Adhesion Molecules; D010320:Parvalbumins; D012794:Sialic Acids; C021319:polysialic acid; D049452:Green Fluorescent Proteins; D013004:Somatostatin; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse
keywords: Cortical interneuron migration; Mouse prefrontal cortex; NCAM; Neural cell adhesion molecule; Parvalbumin; Protein glycosylation; Somatostatin