Severe mental illnesses have been linked to white matter abnormalities, documented by postmortem studies. However, cause and effect have remained difficult to distinguish. CNP (2′,3′-cyclic nucleotide 3′-phosphodiesterase) is among the oligodendrocyte/myelin-associated genes most robustly reduced on mRNA and protein level in brains of schizophrenic, bipolar or major depressive patients. This suggests that CNP reduction might be critical for a more general disease process and not restricted to a single diagnostic category. We show here that reduced expression of CNP is the primary cause of a distinct behavioural phenotype, seen only upon aging as an additional ‘pro-inflammatory hit’. This phenotype is strikingly similar in Cnp heterozygous mice and patients with mental disease carrying the AA genotype at CNP SNP rs2070106. The characteristic features in both species with their partial CNP ‘loss-of-function’ genotype are best described as ‘catatonia-depression’ syndrome. As a consequence of perturbed CNP expression, mice show secondary low-grade inflammation/neurodegeneration. Analogously, in man, diffusion tensor imaging points to axonal loss in the frontal corpus callosum. To conclude, subtle white matter abnormalities inducing neurodegenerative changes can cause/amplify psychiatric diseases.

‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.

In the peripheral nervous system, the 'trigger' of myelination is axon size (>1µm), a threshold mediated by Nrg1 type III on the axon surface 1 . Since Nrg1 is not required for CNS myelination 2 , we asked whether axon size can be experimentally increased here by the absence of PTEN 3 , i.e. with PI(3,4,5)P3 stimulating the AKT1/mTOR pathway ( Fig.1a). To specifically enlarge cerebellar granule cells (GC) and their naturally unmyelinated parallel fiber (Pf) axons, we generated Tg (m6) (Fig.1d).Mutant mice appeared healthy (Supplementary Video1), but cerebellar GC layer (GL) and molecular layer (ML) progressively enlarged ( Fig.1e; Supplementary Fig.1a).Immunostaining of GABAA receptor 6 revealed a gradual size increase of GC somata ( Supplementary Fig.1b). Older mice developed ataxia and tremor (Supplementary Video2), possibly due to hamartomas at advanced age (Supplementary Fig.2; Supplementary Information).The diameter of Pf also increased over time, as quantified by electron microscopy (EM), reaching 0.61±0.009µm in mutants over 0.16±0.002 µm in controls at 1 year of age ( Fig.1f,g; Supplementary Fig.1c). Importantly, radial Pf growth in mutant brains was associated with significant myelination beginning at age P40 (2.30.6% myelinated Pf) and progressing over time (3 months: 9.51% myelinated Pf), up to 3 403% of Pf being myelinated at 1 year with an average g-ratio of 0.84. Myelination was visualized by Gallyas silver impregnation ( Supplementary Fig.3a), anti-CNP immunohistochemistry ( Fig.1h, Supplementary Fig.3b), including whole-mount immunolabelling combined with light sheet and 2-photon microscopy (Supplementary Video3), as well as EM (Fig.1i-k). We determined a 'size threshold' of approximately 0.25 µm for myelination at all ages tested (Fig.1k,l). Myelinated Pf segments were very rarely seen in controls.De novo myelination included the formation of nodes and paranodes with septate -like junctions ( Fig.1j) and the clustering of Caspr and NaV1.6 on axons (Fig.1m,n). GC synaptic contacts to Purkinje cell dendrites were restricted to Pf 'nodal' regions ( Fig.1o; Supplementary Fig.4).The ML harbors normally very few oligodendrocytes and only scattered OPC s, as demonstrated in Plp1-DsRed*Ng2-EYFP double-transgenic mice (Fig.2a). In Pten mutants at P45, mature oligodendrocytes were increased in the GL (+33%) and more prominent in the ML (+750%), yet unaltered in cerebellar white matter (WM) (Fig.2b).To determine whether OPCs proliferate in the ML or are recruited from the GL, we combined immunostaining with BrdU labeling (Fig.2c). After 20 days of daily BrdU injections (P25-45), OPC proliferation (BrdU+,Olig2+) was the same in GL or WM of mutants and controls (Fig.2d). However, OPC proliferation in the mutant ML was 4.4 -fold increased. Even at age 6-7 months, we found a 4.7-fold increase of BrdU+,Olig2+ cells. This suggests that local proliferation is stimulated (directly or indirectly) by GC axon-derived signals, which must still be present at older ages. At that time, oligodendrocyte lineage cel...

Subtle white matter abnormalities have emerged as a hallmark of brain alterations in magnetic resonance imaging or upon autopsy of mentally ill subjects. However, it is unknown whether such reduction of white matter and myelin contributes to any disease‐relevant phenotype or simply constitutes an epiphenomenon, possibly even treatment‐related. Here, we have re‐analyzed Mbp heterozygous mice, the unaffected parental strain of shiverer, a classical neurological mutant. Between 2 and 20 months of age, Mbp+/‐ versus Mbp+/+ littermates were deeply phenotyped by combining extensive behavioral/cognitive testing with MRI, 1H‐MR spectroscopy, electron microscopy, and molecular techniques. Surprisingly, Mbp‐dependent myelination was significantly reduced in the prefrontal cortex. We also noticed a mild but progressive hypomyelination of the prefrontal corpus callosum and low‐grade inflammation. While most behavioral functions were preserved, Mbp+/‐ mice exhibited defects of sensorimotor gating, as evidenced by reduced prepulse‐inhibition, and a late‐onset catatonia phenotype. Thus, subtle but primary abnormalities of CNS myelin can be the cause of a persistent cortical network dysfunction including catatonia, features typical of neuropsychiatric conditions. GLIA 2016;64:2025–2040

Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte-specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation.