Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

Dysfunctional glutamatergic neurotransmission in the pathogenesis of obsessive-compulsive disorder (OCD) was postulated on the basis of magnetic resonance imaging studies.^1,2 This hypothesis was subsequently supported by animal models based on abnormal glutamate neurotransmission that contributed to OCD spectrum–like phenotypes,^3,4 case reports of beneficial therapeutic effects of riluzole (an antiglutamatergic agent) on treatment-resistant OCD,⁵ and elevated glutamate levels in the cerebrospinal fluid of OCD probands.⁶ From a genetic perspective, investigation of glutamatergic genes in OCD therefore represents a plausible biological candidate approach given this disorder's high heritability and risk to relatives.^7,8 Indeed, studies have shown positive associations of glutamate receptor genes with OCD.^9,10

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric illness with strong segregation data indicative of major genetic contributions. Association analyses of common functional variants of the serotonin transporter gene (SLC6A4), a long-standing OCD candidate, have so far been inconsistent. Here, we set out to investigate the role of additional functional SLC6A4 loci in OCD. We describe a common, functional C > T single nucleotide polymorphism, rs25532, located less than 150 nucleotides centromeric of the serotonin transporter-linked polymorphic region indel known as 5-HTTLPR. The minor allele of rs25532 significantly decreased luciferase reporter gene expression levels by 15–80%, depending on 5-HTTLPR allele background and cell type. Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus association with OCD in a large case–control sample. Remarkably, the haplotype significantly overrepresented in probands contained the higher-expressing allele at each locus, supporting the notion of increased serotonin transporter functioning being pathogenetically involved in OCD. Conditional haplotype analyses with the software WHAP revealed that this association is primarily driven by 5-HTTLPR, rs25532 and rs16965628. Our results contribute to a better understanding of SLC6A4 expression genetics and provide a functional haplotype framework for future serotonin-related studies.

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)_2A/2C agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A₂ (PLA₂)] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA₂ and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT_2A or 5-HT_2C receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT_2C receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT_2A receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT_2C receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT_2C receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA₂-specific at the 5-HT_2A receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT_2A receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.