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

Diffusible factors, including netrins and semaphorins, are believed to be i mportant cues for the formation of neural circuits in the forebrain, Here w e have examined the role of netrin 1 in the development of hippocampal conn ections, We show that netrin I 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 misori entation of fiber tracts and pathfinding errors, as detected with antibodie s against the surface proteins TAG-1, L1 and DCC, DiI injections show that hippocampal commissural axons do not cross the midline in these mutants. In stead, when axons approach the midline, they turn ventrally and form a mass ive aberrant projection to the ipsilateral septum, In addition, both the ip silateral entorhino-hippocampal and the CA3-to-CA1 associational projection s show an altered pattern of layer-specific termination in netrin 1-deficie nt mice. Finally, optical recordings with the Ca2+ indicator Fura 2-AM show that spontaneous neuronal activity is reduced in the septum of netrin 1-mu tant mice, We conclude that netrin 1 is required not only fbr the formation of crossed connections in the forebrain, but also for the appropriate laye r-specific targeting of ipsilateral projections and for the control of norm al levels of spontaneous neural activity.