Aberrant development of hippocampal circuits and altered neural activity in netrin 1-deficient mice

• Published in: Development (Cambridge) Vol. 127; no. 22; pp. 4797 - 4810
• Main Authors: Barallobre, M J, Del Río, J A, Alcántara, S, Borrell, V, Aguado, F, Ruiz, M, Carmona, M A, Martín, M, Fabre, M, Yuste, R, Tessier-Lavigne, M, Soriano, E
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 15.11.2000
• Subjects: Animals; Animals, Newborn; Axons - ultrastructure; Calcium Signaling; Cell Adhesion Molecules - physiology; Dcc gene; DCC protein; DCC Receptor; DCC receptors; Gene Expression Regulation, Developmental; Hippocampus - abnormalities; Hippocampus - growth & development; Hippocampus - physiopathology; In Vitro Techniques; L1 protein; Mice; Mice, Knockout; Mice, Mutant Strains; Nerve Growth Factors - deficiency; Nerve Growth Factors - genetics; Nerve Growth Factors - physiology; netrin 1 gene; Netrin-1; Neural Pathways - abnormalities; Neural Pathways - growth & development; Neural Pathways - physiopathology; Receptors, Cell Surface; TAG-1 protein; Tumor Suppressor Proteins
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.127.22.4797

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.