Crucial roles of Robo proteins in midline crossing of cerebellofugal axons and lack of their up-regulation after midline crossing

<p>Abstract</p> <p>Background</p> <p>Robo1, Robo2 and Rig-1 (Robo3), members of the Robo protein family, are candidate receptors for the chemorepellents Slit and are known to play a crucial role in commissural axon guidance in the spinal cord. However, their roles at other axial levels remain unknown. Here we examine expression of Robo proteins by cerebellofugal (CF) commissural axons in the rostral hindbrain and investigate their roles in CF axon pathfinding by analysing Robo knockout mice.</p> <p>Results</p> <p>We analysed the expression of Robo proteins by CF axons originating from deep cerebellar neurons in rodent embryos, focusing on developmental stages of their midline crossing and post-crossing navigation. At the stage of CF axon midline crossing, mRNAs of Robo1 and Robo2 are expressed in the nuclear transitory zone of the cerebellum, where the primordium of the deep cerebellar nuclei are located, supporting the notion that CF axons express Robo1 and Robo2. Indeed, immunohistochemical analysis of CF axons labelled by electroporation to deep cerebellar nuclei neurons indicates that Robo1 protein, and possibly also Robo2 protein, is expressed by CF axons crossing the midline. However, weak or no expression of these proteins is found on the longitudinal portion of CF axons. In <it>Robo1</it>/<it>2 </it>double knockout mice, many CF axons reach the midline but fail to exit it. We find that CF axons express Rig-1 (Robo3) before they reach the midline but not after the longitudinal turn. Consistent with this <it>in vivo </it>observation, axons elicited from a cerebellar explant in co-culture with a floor plate explant express Rig-1. In <it>Rig-1 </it>deficient mouse embryos, CF axons appear to project ipsilaterally without reaching the midline.</p> <p>Conclusion</p> <p>These results indicate that Robo1, Robo2 or both are required for midline exit of CF axons. In contrast, Rig-1 is required for their approach to the midline. However, post-crossing up-regulation of these proteins, which plays an important role in spinal commissural axon guidance, does not appear to be required for the longitudinal navigation of CF axons after midline crossing. Our results illustrate that although common mechanisms operate for midline crossing at different axial levels, significant variation exists in post-crossing navigation.</p

Mechanisms of Homeostatic Control of Neuronal Intrinsic Excitability

A neuron’s identity and function are dictated by its electrophysiological signature. The firing pattern of a neuron emerges from the particular combination of ion channels in its membrane. A neuron can “tune” the combination of ionic conductances that it expresses to return back to its target excitability when faced with changing conditions. While this phenomenon of firing rate homeostasis (FRH) is well-established, the mechanisms underlying it have remained mysterious. A prevalent theory proposes that firing rates are maintained through regulatory feedback relying on the detection and stabilization of a single variable, calcium. Within the framework of this theory, all perturbations with equivalent effects on neuronal activity should invoke the same homeostatic response. In a direct test of this hypothesis, we compared two independent experimental manipulations to the Shal potassium ion channel. While we observed FRH following either a conductance-blocking mutation or complete elimination of the Shal protein, the compensating currents and the molecular mechanisms underlying the homeostatic response differed between the two conditions. Neurons lacking the Shal protein enacted transcriptional upregulation of the ion channels Slo, Shab, and Shaker, in part through the transcription factor Krüppel. In contrast, neurons with a non-conducting Shal channel compensated through non-transcriptional modification of a different set of conductances. We propose that neurons have multiple, separable homeostatic signaling systems, including proteostatic and activity-sensitive feedback systems. We then further expand on the mechanisms of FRH to include a role for the Notch signaling system. This canonical pathway for neural development is reactivated following loss of Shal and is necessary for stabilization of firing rates. We propose a model in which the loss of the transcription factor Nerfin-1 de-represses the Notch, and Notch cleavage by presenilin followed by cooperation of NICD with Su(H) results in transcriptional rebalancing of ion channels. These findings have implications for the pathophysiology of human channelopathies and Alzheimer’s disease

The Impact of Diabetes on Hippocampus

Maternal Diabetes is one of the most common metabolic disorders resulting an increased risk of abnormalities in the developing fetus and offspring. It is estimated that the prevalence of diabetes during pregnancy among women in developing countries is approximately 4.5 percent and this range varies between 1 to 14 percent in different societies. According to earlier studies, diabetes during pregnancy is associated with an increased risk of maternal and child mortality and morbidity as well as major congenital anomalies including central nervous system (CNS) in their offspring. Multiple lines of evidence have suggested that infants of diabetic women are at risk of having neurodevelopmental sequelae. Previous studies reveal that the offspring of diabetic mothers exhibit disturbances in behavioral and intellectual functioning. In the examination of cognitive functioning, a poorer performance was observed in the children born to diabetic mothers when compared with the children of non-diabetic mothers. Therefore, it is important to study the possible effects of maternal diabetes on the hippocampus of these infants

Hippocampus

The hippocampus is a bicortical structure with extensive fiber connections with multiple brain regions. It is involved in several functions, such as learning, memory, attention, emotion, and more. This book covers various aspects of the hippocampus including cytoarchitecture, functions, diseases, and treatment. It highlights the most advanced findings in research on the hippocampus. It discusses circuits, pattern formation process of grid cells, and zinc dynamics of the hippocampus. The book also addresses the tau pathology and circRNAs related to Alzheimer’s disease and potential treatment strategies. It is a useful resource for general readers, students, and researchers