Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons

Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This understanding will facilitate to discern the role of nucleocytoplasmic transport in the differential vulnerability of neurons to ALS and to develop therapeutic approaches and biomarkers in ALS. Here, we ascertain Ranbp2 function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified Cd11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. This immunogenic phenotype was accompanied by the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neural-type selective substrates. Metabolic and immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuroglial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of ALS.

Dendritic Excitability and Neuronal Morphology as Determinants of Synaptic Efficacy

The ability to trigger neuronal spiking activity is one of the most important functional characteristics of synaptic inputs and can be quantified as a measure of synaptic efficacy (SE). Using model neurons with both highly simplified and real morphological structures (from a single cylindrical dendrite to a hippocampal granule cell, CA1 pyramidal cell, spinal motoneuron, and retinal ganglion neurons) we found that SE of excitatory inputs decreases with the distance from the soma and active nonlinear properties of the dendrites can counterbalance this global effect of attenuation. This phenomenon is frequency dependent, with a more prominent gain in SE observed at lower levels of background input–output neuronal activity. In contrast, there are no significant differences in SE between passive and active dendrites under higher frequencies of background activity. The influence of the nonuniform distribution of active properties on SE is also more prominent at lower background frequencies. In models with real morphologies, the effect of active dendritic conductances becomes more dramatic and inverts the SE relationship between distal and proximal locations. In active dendrites, distal synapses have higher efficacy than that of proximal ones because of arising dendritic spiking in thin branches with high-input resistance. Lower levels of dendritic excitability can make SE independent of the distance from the soma. Although increasing dendritic excitability may boost SE of distal synapses in real neurons, it may actually reduce overall SE. The results are robust with respect to morphological variation and biophysical properties of the model neurons. The model of CA1 pyramidal cell with realistic distributions of dendritic conductances demonstrated important roles of hyperpolarization-activated (h-) current and A-type K+ current in controlling the efficacy of single synaptic inputs and overall SE differently in basal and apical dendrites.