Abnormal myelin development and the mental diseases
Although SCZ and BD account for 2% − 4% of the world population, the pathogenesis and treatment of SCZ and BD are unclear and unsatisfied [27, 28]. Strikingly, imaging and autopsy studies not only show that abnormal white matter is a common neurobiological change in BD and SCZ patients but also reveal that SCZ patients are accompanying with dysregulation of oligodendrocyte (OL) related processes, such as myelination developmental disorder, abnormal expression of myelination gene and number changes of OLs[29, 30]. However, the molecular between abnormal myelination and the two mental diseases is unclear.
The myelin sheath is composed of bilayer lipids as the frame, with proteins embedded as one of the plasma membranes. Most of the proteins in the myelin sheath are transmembrane proteins, such as MBP and proteolipid protein. In these proteins, MBP accounts for 30% of the total myelin protein in the CNS and is critical for myelination [31, 32]. MBP expression was enhanced in Tmem108 mutant mice via WB and IHC staining, and the mutant mice also exhibited hypermyelination by electron microscopy.
The myelin sheath in mature OL acts as an external insulator for current conduction, facilitating rapid saltatory impulse conduction with reduced axonal diameters. Moreover, myelin also provides essential nutritional support for myelinated neurons. Myelinated fibers are widely distributed in the brain, and myelin sheath is essential for maintaining neural circuits. Accordingly, hypomyelination or hypermyelination of OL deriving from abnormal myelination may be one of the bases of cognitive impairment in SCZ and BD, also relating to poor prognosis [29, 33].
Potential multiple functions of Tmem108 in the CNS
Tmem108, also known as Retrolinkin [19, 34, 35], is located on human chromosome 3q21. GWAS found that TMEM108 is not only related to substance addiction , smoking withdrawal , and alcohol addiction [38–41], but also is a susceptibility gene of SCZ [11, 12, 14] and BD [11–13].
O'Donovan et al. found that the SNP (rs7624858) mutation in the intron of Tmem108 is related to SCZ  and speculated that the site caused Tmem108 to become a susceptibility gene of SCZ by affecting gene expression. Jiao et al. disclosed that Tmem108 mutant mice are impaired in spatial memory, and fear startles contextual memory and is more sensitive in PPI performance , a classic and plausible psychophysiological measurement of sensorimotor gating for SCZ in rodents and humans [42, 43].
The nature of the severe mental illness has been debated for more than one century. According to the prevailing manuals, International Classification of Diseases, BD, and schizophrenia reveal striking similarities, and the difference is that sensory gating and cognitive impairments are less pronounced in BD patients . BD and schizophrenia consistently ranked among the leading causes of disability worldwide [45, 46], with similarities across multiple levels, such as overlapping brain structural [47, 48] and shared genetic risk factors [49–52]. BD and schizophrenia are severe psychiatric disorders with high heritability, but to date, unknown etiology, sharing genetic risk factors, and a possible illness mechanism is abnormal myelination [10, 53, 54].
Although Tmem108 mutant impairs adult neurogenesis of the mice, it does not induce depression-like behavior but stirs manic-like behavior, suggesting Tmem108 is higher correlating with BD than depression . Strikingly, one recent GWAS screened BD risk loci in the Han Chinese population, covering 1822 BD patients and 4650 control individuals, and the data was replicated analysis. After finally multiple analyses between Han Chinese and European populations, a new SNP (rs9863544) in BD patients were found, locating in the upstream regulatory region of the Tmem108 gene . Tmem108 expression change may be one of the onset reasons of the related psychiatry diseases.
Researchers have debated whether severe, chronic irritability without episodic mania constitutes a developmental phenotype of BD . Neurobiological models of BD emphasize white matter aberrant development, and white matter microstructure is often described as fractional anisotropy, which is positively associated with the smaller axon diameter and increased axon packing density .
The potential molecular mechanism of Tmem108 regulating myelination
In 2014, Zhang Y et al. purified eight representative cell populations in the CNS and generated the RNA transcriptome database for the different types of cells . Intriguingly, Tmem108 is expressed in the neurons as in previous research and has a higher expression in the OL lineage cells than in the neurons, significantly much higher in newly formed OL than in any other cells (Fig. S1). Tmem108 mutant mice had manic-like behavior and were more active than the control group in forced swimming and tail suspension experiments . Moreover, 24-hour restraint exacerbated the manic-like behavior of the mutant mice, and the mutant mice were easily induced epilepsy by pilocarpine, which may be partially related to the abnormal myelination.
Although Tmem108 expression was low in the CC of the mice without detectable by X-gal staining, its expression was high in young wild-type mice and could be colocalized with Olig2 positive cells by utilizing the gene reporter mice. To explore how Tmem108 inhibited proliferation and myelination of OL cells, gene expression with myelination regulation  was detected by qPCR. Intriguingly, Tcf4 was also expressed highly besides myelin regulatory factor (Myrf) in all three brain areas of Tmem108 mutant mice (Fig S4). In previous research, Tmem108 was reported to involve adult neurogenesis by the Wnt signaling pathway. In CC, most genes with significantly altering expression were downstream of the Wnt signaling pathway, such as Id2, Id4, Tcf4, and Tcf7l2.
Wnt signaling plays a complicated role in the OL myelination, depending on the final effector in the signaling pathway. Canonical Wnt/β-catenin signaling pathway strongly inhibits differentiation [56–58]. Under Wnt3a treatment, differentiation of OPC is strongly delayed or blocked , recruiting Tcf4/Tcf7l2 to β-catenin target genes to promote proliferation [57, 59]. ID2 and ID4 are regarded as the potential targets of Wnt/β-catenin/Tcf4 signals in OL development.
Not surprisingly, β-catenin decrease leads to enhancing the premyelinating OL. However, OL differentiation is not enhanced but reduced in Tcf7l2 knockout mice [56, 59], and differentiation is delayed in β-catenin inactivated mice , indicating the complexity of β-catenin /Tcf7l2. The potential mechanism is Tcf7l2 interacting with HDAC1 (Histone deacetylases 1) and HDAC2, which repress the expression of differentiation inhibitors . Thereby, Tcf7l2 acts like a molecular switch, blocking or promoting OL differentiation by associating with the different binding partners . We speculated that Tmem108 regulated proliferation and myelination via the Wnt signaling pathway depending on different effectors, which needs further research in vivo and in vitro.