title: Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice.
abstract: Diffusible factors, including netrins and semaphorins, are believed to be important cues for the formation of neural circuits in the forebrain. Here we have examined the role of netrin 1 in the development of hippocampal connections. We show that netrin 1 and its receptor, Dcc, are expressed in the developing fimbria and in projection neurons, respectively, and that netrin 1 promotes the outgrowth of hippocampal axons in vitro via DCC receptors. We also show that the hippocampus of netrin 1-deficient mice shows a misorientation of fiber tracts and pathfinding errors, as detected with antibodies against the surface proteins TAG-1, L1 and DCC. DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. Instead, when axons approach the midline, they turn ventrally and form a massive aberrant projection to the ipsilateral septum. In addition, both the ipsilateral entorhino-hippocampal and the CA3-to-CA1 associational projections show an altered pattern of layer-specific termination in netrin 1-deficient mice. Finally, optical recordings with the Ca(2+) indicator Fura 2-AM show that spontaneous neuronal activity is reduced in the septum of netrin 1-mutant mice. We conclude that netrin 1 is required not only for the formation of crossed connections in the forebrain, but also for the appropriate layer-specific targeting of ipsilateral projections and for the control of normal levels of spontaneous neural activity.
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona E-08028, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Barallobre
authors.forename: J A
authors.initials: JA
authors.lastname: Del Río
authors.forename: S
authors.initials: S
authors.lastname: Alcántara
authors.forename: V
authors.initials: V
authors.lastname: Borrell
authors.forename: F
authors.initials: F
authors.lastname: Aguado
authors.forename: M
authors.initials: M
authors.lastname: Ruiz
authors.forename: M A
authors.initials: MA
authors.lastname: Carmona
authors.forename: M
authors.initials: M
authors.lastname: Martín
authors.forename: M
authors.initials: M
authors.lastname: Fabre
authors.forename: R
authors.initials: R
authors.lastname: Yuste
authors.forename: M
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: E
authors.initials: E
authors.lastname: Soriano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000648:ultrastructure; D020013:Calcium Signaling; D015815:Cell Adhesion Molecules / Q000502:physiology; D000075389:DCC Receptor; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000002:abnormalities* / Q000254:growth & development / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000075388:Netrin-1; D009434:Neural Pathways / Q000002:abnormalities / Q000254:growth & development / Q000503:physiopathology; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins
chemical_list: D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1