Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts.
Manganese enhanced MRI (MEMRI) offers many possibilities such as tract tracing and functional imaging in vivo. Mn is however neurotoxic and may induce symptoms similar to those associated with Parkinson's disease (manganism). The mechanisms of Mn-induced neurotoxicity are not clear. In this study, we combine synchrotron X-ray fluorescence microprobe (SR-XRF) and MEMRI techniques to investigate spatial distribution of Mn within the rat hippocampus and how Mn interacts with Ca, Fe and Zn at a cellular level. Images were acquired in the rat hippocampus (n=23) and using two injection routes: intra-cerebral (MnCl(2): 50 mM, 10 μL) and intra-peritoneal (MnCl(2): 100 mM, 30 mg/kg). For both injection routes, Mn is found in dentate gyrus and in CA3: control: 2.5 ± 1.6, intra-peritoneal: 5.0 ± 2.4, and intra-cerebral: 25.1 ± 9.2 μg/g. Mn follows Zn distribution and has a negative impact on the total amount of Zn and Fe. The Mn-enhanced MRI contrast is well correlated with the total Mn amount measured with SR-XRF (R(2)=0.93; p<0.002). After intra-cerebral injection, the hippocampal fissure is found to accumulate a large amount of Mn and yields a hypointense MRI signal, which may be ascribed to a reduction in T2. This study shows that SR-XRF is well suited to investigate Mn distribution at a mesoscale and that MRI is sensitive to low Mn concentrations. As perturbations in metal homeostasis may alter brain function, the injected dose of Mn in MEMRI studies needs to be carefully adjusted to obtain reliable functional information.
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