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The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptors are the CB 1 cannabinoid receptors; however, CB 2 cannabinoid receptors, transient receptor potential channels, and peroxisome proliferator activated receptors are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide). Despite similarities in chemical structure, 2-arachidonoyl glycerol and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiologic and pathophysiologic roles to these two endocannabinoids. As a result of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiologic and pathophysiologic roles of the ECS. This review provides an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: Alterations in dendritic spine densities and morphologies have been correlated with the abnormal functioning of the synapse. Specifically the metabotropic glutamate receptor 5 (mGluR5) has been implicated in dendrogenesis and spineogenesis, since its activation triggers various signaling cascades that have been demonstrated to play roles in synaptic maturation and plasticity. Here we used the Golgi impregnation technique to analyze the dendritic spines of mGluR5−/− knockout mice in comparison to their heterozygote mGluR5+/− littermates. mGluR5−/− mice had elevated spine densities irrespective of spine type or location along their dendritic trees in comparison to mGluR5+/− animals. Such anatomical changes may underlie the hyperexcitability observed in mGluR5 total knockout mice. [Copyright &y& Elsevier]

We tested the efficacy of 4′-fluorocannabidiol (4′-F-CBD), a semisynthetic cannabidiol derivative, and HU-910, a cannabinoid receptor 2 (CB2) agonist in resolving l -DOPA-induced dyskinesia (LID). Specifically, we were interested in studying whether these compounds could restrain striatal inflammatory responses and rescue glutamatergic disturbances characteristic of the dyskinetic state. C57BL/6 mice were rendered hemiparkinsonian by unilateral striatal lesioning with 6-OHDA. Abnormal involuntary movements were then induced by repeated i.p. injections of l -DOPA + benserazide. After LID was installed, the effects of a 3-day treatment with 4′-F-CBD or HU-910 in combination or not with the TRPV1 antagonist capsazepine (CPZ) or CB2 agonists HU-308 and JWH015 were assessed. Immunostaining was conducted to investigate the impacts of 4′-F-CBD and HU-910 (with CPZ) on inflammation and glutamatergic synapses. Our results showed that the combination of 4′-F-CBD + CPZ, but not when administered alone, decreased LID. Neither HU-910 alone nor HU-910+CPZ were effective. The CB2 agonists HU-308 and JWH015 were also ineffective in decreasing LID. Both combination treatments efficiently reduced microglial and astrocyte activation in the dorsal striatum of dyskinetic mice. However, only 4′-F-CBD + CPZ normalized the density of glutamate vesicular transporter-1 (vGluT1) puncta colocalized with the postsynaptic density marker PSD95. These findings suggest that 4′-F-CBD + CPZ normalizes dysregulated cortico-striatal glutamatergic inputs, which could be involved in their anti-dyskinetic effects. Although it is not possible to rule out the involvement of anti-inflammatory mechanisms, the decrease in striatal neuroinflammation markers by 4′-F-CBD and HU-910 without an associated reduction in LID indicates that they are insufficient per se to prevent LID manifestations. [Display omitted] • The semisynthetic cannabinoid 4′-F-CBD decreases LID if associated with capsazepine. • HU-910 failed to alleviate LID despite restraining striatal glial activation. • 4′-F-CBD does not act only on pro-inflammatory pathways associated with dyskinesia. • LID reduction by 4′-F-CBD aligns with corticostriatal signaling normalization. • 4′-F-CBD may help treat LID manifestations. [ABSTRACT FROM AUTHOR]

Highlights: [•] Neurons require a ‘maintenance plan’ that enables them to endure daily wear and tear. [•] NMNATs function as NAD synthesizing enzymes and chaperones. [•] Loss of NMNAT causes rapid and severe neurodegeneration. [•] NMNATs have the broadest and most potent neuroprotective effects. [•] Alzheimer's Disease, Parkinson's Disease, and other neurodegenerative disorders are accompanied by downregulation of NMNAT. [ABSTRACT FROM AUTHOR]

Abstract: Very-low-density lipoprotein receptor (VLDLR) is a multi ligand apolipoprotein E (apoE) receptor and is involved in brain development through Reelin signaling. Different forms of VLDLR can be generated by alternative splicing. VLDLR-I contains all exons. VLDLR-II lacks an O-linked sugar domain encoded by exon 16, while VLDLR-III lacks the third complement-type repeat in the ligand binding domain encoded by exon 4. We quantitatively compared lipoprotein binding to human VLDLR variants and analyzed their mRNA expression in both human cerebellum and mouse brain. VLDLR-III exhibited the highest capacity in binding to apoE enriched β-VLDL in vitro and was more effective in removing apoE containing lipoproteins from the circulation than other variants in vivo. In human cerebellum, the major species was VLDLR-II, while the second most abundant species was a newly identified VLDLR-IV which lacks both exon 4 and 16. VLDLR-I was present at low levels. In adult mice, exon 4 skipping varied between 30 and 47% in different brain regions, while exon 16 skipping ranged by 51–76%. Significantly higher levels of VLDLR proteins were found in mouse cerebellum and cerebral cortex than other regions. The deletions of exon 4 and exon 16 frequently occurred in primary neurons, indicating that newly identified variant VLDLR-IV is abundant in neurons. In contrast, VLDLR mRNA lacking exon 4 was not detectable in primary astrocytes. Such cell type-specific splicing patterns were found in both mouse cerebellum and cerebral cortex. These results suggest that a VLDLR variant lacking the third complement-type repeat is generated by neuron-specific alternative splicing. Such differential splicing may result in different lipid uptake in neurons and astrocytes. [Copyright &y& Elsevier]