Neuroscience
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Huntingtin-associated protein 1 (HAP1) is a neuronal interactor with causatively polyglutamine (polyQ)-expanded huntingtin in Huntington's disease and also associated with pathologically polyQ-expanded androgen receptor (AR) in spinobulbar muscular atrophy (SBMA), being considered as a protective factor against neurodegenerative apoptosis. In normal brains, it is abundantly expressed particularly in the limbic-hypothalamic regions that tend to be spared from neurodegeneration, whereas the areas with little HAP1 expression, including the striatum, thalamus, cerebral neocortex and cerebellum, are targets in several neurodegenerative diseases. While the spinal cord is another major neurodegenerative target, HAP1-immunoreactive structures have yet to be determined there. ⋯ Double-immunostaining for HAP1 and AR demonstrated that more than 80% of neurons expressed both in the same areas. In contrast, HAP1 was specifically lacking in the lamina IX motoneurons with or without AR expression. The present study first demonstrated that HAP1 is abundantly expressed in spinal neurons of the somatosensory, viscerosensory, and autonomic regions but absent in somatomotor neurons, suggesting that the spinal motoneurons are, due to lack of putative HAP1 protectivity, more vulnerable to stresses in neurodegenerative diseases than other HAP1-expressing neurons probably involved in spinal sensory and autonomic functions.
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We examined the contribution of the sodium channel isoform Nav1.8 to retinal function using the specific blocker A803467. We found that A803467 has little influence on the electroretinographic (ERG) a- and b-waves, but significantly reduces the oscillatory potentials to 40-60% of their original amplitude, with significant changes in implicit time in the rod-driven range. To date, only two cell types were found in mouse to express Nav1.8; the starburst amacrine cells (SBAC), and a subtype of retinal ganglion cells (RGC). ⋯ We have previously shown that RGCs have only a minor contribution to the oscillatory potentials (Smith et al., 2014), therefore suggesting that starburst amacrine cells might be a significant contributor to this ERG component. Targeting SBACs with the cholinergic neurotoxin ethylcholine mustard aziridinium (AF64A) caused reduction in the amplitude of the OPs similar to A803467. Our results, both using the ERG and MEA recordings from retina ganglion cells, suggest that Nav1.8 plays a role in modulating specific aspects of the retinal physiology and that SBACs are a fundamental cellular contributor to the OPs in mice, a clear demonstration of the dichotomy between ERG b-wave and oscillatory potentials.
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After peripheral nerve injury, transected fibers distal to the lesion are disconnected from the neuronal body. This results in target denervation but also massive stripping of the central synapses of axotomized motoneurons, disrupting spinal circuits. Even when axonal regeneration is successful, the non-specific target reinnervation and the limited rebuilding of spinal circuits impair functional recovery. ⋯ Treatment with the TrkB agonist at a low dose, but not at a high dose, prevented the decrease of excitatory glutamatergic synapses, and both doses increased the density of inhibitory synapses. TrkB inactivation counteracted only some of the positive effects exerted by exercise after nerve injury, such as maintenance of excitatory synapses surrounding motoneurons. Therefore, specific regimes of physical exercise are a better strategy to attenuate the alterations that motoneurons suffer after axotomy than pharmacological modulation of the TrkB pathway.
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Endocannabinoids and somatostatin play critical roles in several pathophysiological conditions via binding to different receptor subtypes. Cannabinoid receptor 1 (CB1R) and somatostatin receptors (SSTRs) are expressed in several brain regions and share overlapping functions. Whether these two prominent members of G-protein coupled receptor (GPCR) family interact with each other and constitute a functional receptor complex is not known. ⋯ Furthermore, concurrent receptor activation led to preferential formation of SSTR5 homodimer and dissociation of CB1R homodimer. We also discovered that second messenger cyclic adenosine monophosphate and downstream signaling pathways were modulated in a SSTR5-dominant and concentration-dependent manner in the presence of receptor specific agonist. In conclusion, with predominant role of SSTR5, the functional consequences of crosstalk between SSTR5 and CB1R resulting in the regulation of receptor trafficking and signal transduction pathways open new therapeutic avenue in cancer biology and excitotoxicity.